The Clock Is Ticking: The Case for Achieving More Rapid Control of Hypertension

Abstract

Start low, go slow for many years has been the paradigm guiding drug treatment of hypertension. Patients start on low doses of a single medication; if control is not achieved the dosage is gradually increased or additional medications are started. Yet studies persistently show that by this method the majority of patients with hypertension do not achieve adequate blood pressure control.1 While there are many reasons, including patient nonadherence with recommended therapies and resistant hypertension,2, 3 a growing literature highlights the role of therapeutic inertia.4, 5 Consistent with the go slow paradigm, patients with elevated blood pressures are seen repeatedly by clinicians but therapy is not intensified. As a result, many patients with inadequate blood pressure control are treated with only one or two antihypertensive medications, often at low dosages, for prolonged periods. The evidence now suggests that to improve cardiovascular outcomes, we require a new paradigm that emphasizes rapid achievement of blood pressure control.6 We believe that central to this paradigm should be an explicit expectation of the timeframe in which blood pressure control should be achieved. While existing guidelines increasingly emphasize the use of drug combinations to achieve more rapid control, they are surprisingly quiet on this issue of time to control. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommends: “once antihypertensive drug therapy is initiated, most patients should return for follow-up and adjustment of medications at approximately monthly intervals until the blood pressure goal is achieved,” and that more frequent visits will be necessary for patients with stage 2 hypertension.1 Recently published guidelines from the European Society of Hypertension and European Society of Cardiology make no reference to the time between follow-up visits or to achieve control.7 We now argue for an explicit expectation that anticipates blood pressure control within 3 months of initiating therapy. Recent hypertension clinical trials with major cardiovascular endpoints have highlighted two key facts about blood pressure control. First, early differences in achieved blood pressures among comparative treatment arms, even when managed by experienced clinician-investigators, are not easily eliminated despite continuing efforts to reach specified targets. Thus, initial failure to treat aggressively makes it less likely that control will ever be achieved. Second, the resulting small differences in achieved blood pressures account for significant differences in clinical event rates. One strong example of this was the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), in which high risk hypertensive patients randomized to diuretic-based treatment had persistently lower blood pressures than those starting with either an angiotensin-converting enzyme (ACE) inhibitor or a calcium channel blocker.8 The resulting blood pressure inequalities among the treatment groups, which were most prominent in the early study months, remained throughout the 5 year trial despite repeated exhortations to investigators to seek blood pressure control. The effects on major cardiovascular endpoints of the speed and completeness of blood pressure control were explored in the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial.9 In a cohort of hypertensive patients at high cardiovascular risk, a calcium channel blocker achieved greater blood pressure reductions in the early part of the study than an angiotensin receptor blocker, which persisted for the 5-year duration of the study. This difference in achieved blood pressure appeared to account for significant differences in clinical events; when patients from the two study groups were matched on the basis of identical achieved blood pressures as well as other key clinical and demographic features, there were no endpoint differences between the treatments.10 The importance of achieving systolic blood pressure control (<140 mm Hg), regardless of drug assignment, within the study’s initial 6-month treatment titration period was also demonstrated. Subsequent fatal and nonfatal cardiovascular events were sharply lower, with a hazard ratio of 0.75 in patients achieving blood pressure control as compared with those who did not.9 Indeed, there was an indication that blood pressures achieved by just 1 month of study treatment were predictive of outcomes during the following 5 years. Another high profile hypertension outcomes study affected by early blood pressure differences between treatment groups was the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) in which the amlodipine-perindopril arm had a 5.9/2.4 mm Hg lower blood pressure at 3 months compared to atenolol-bendroflumethiazide.11 This trial was stopped earlier than planned when the safety committee noted that mortality and other endpoints were higher in patients randomized to β-blocker/thiazide treatment than in those randomized to calcium channel blocker/ACE inhibitor treatment. At least part of these differences in event rates could be explained by the differences in blood pressure control.11 A concern when starting antihypertensive therapy is an excessive fall in blood pressure. Certainly, this was an issue with the drugs used 3 or 4 decades ago that worked primarily by interrupting the sympathetic nervous system. The traditional injunction to start low, go slow was appropriate with drugs that could produce dizziness and postural hypotension. This concern, however, is less justified with modern drugs. For instance, in the registration studies performed with the combination of irbesartan and hydrochlorothiazide in patients with severe hypertension (baseline diastolic blood pressures >110 mm Hg), there were few symptomatic complaints when therapy was started with this combination.12 In only 3 out of 328 patients was hypotension observed, and even then only after protocol-mandated up-titration to the maximum dose in patients who had already achieved major blood pressure reductions with the starting dose. A further study in patients with less severe hypertension provided additional reassurance.13 Despite lower baseline blood pressure values, there was a similarly low incidence of observed hypotension, again only after mandated titration to the maximum combination dose. A recent report of a clinical trial in which hypertensive patients were exposed to initial therapy with maximum doses of a calcium channel blocker/angiotensin receptor blocker combination has provided further confirmation of safety.14 Safety concerns may be especially great in elderly populations with isolated systolic hypertension—a group with the lowest rates of blood pressure control and the greatest absolute benefit with effective blood pressure reduction.1 Although lower initial medication doses may sometimes be indicated to minimize symptoms in elderly hypertensive patients, ultimately most will require and tolerate standard doses and multiple drugs to reach blood pressure targets. In the Hypertension in the Very Elderly Trial (HYVET) (≥80 years), combination therapy was used in almost 3 out of 4 participants because of the difficulty in achieving goal blood pressure even though the target systolic blood pressure was <150 mm Hg, and side effects were no more frequent than in the control group.15 There are no randomized clinical trials to date supporting lowering systolic blood pressure below 140 mm Hg in elderly patients.16 Monotherapy with a diuretic, as recommended in past and present guidelines for initiation of therapy, may in fact create greater safety issues than starting with a combination. Diuretics can produce hypovolemia, creating a risk of acute hypotension when blockers of the renin-angiotensin system are later added. Thiazides as single agents can also cause unwanted metabolic changes like hypokalemia or hyperglycemia, which are at least partly prevented by concomitant treatment with renin-angiotensin system blockers.17 Results from early clinical trials may have misleadingly conveyed the impression that blood pressure control cannot be achieved despite years of therapy. In ALLHAT, control was achieved in 66% of patients after 5 years of follow-up.8 However, control rates were only 50% at 6 months and 55% at 1 year. Moreover, even in the rigorous setting of this clinical trial, failures to intensify therapy despite inadequate control were frequent and it was judged “very likely that better blood pressure control rates could have been achieved if therapy were intensified more consistently for persistent systolic blood pressures ≥140 mm Hg.”8 Higher rates of control in shorter time periods have been seen in more recent clinical trials. For example, a recent review of 9 clinical trials highlighted that among hypertensive patients with diastolic blood pressures between 95 and 110 mm Hg, control (<140/90 mm Hg) was achieved within 8 weeks for 74.6% of patients initiating valsartan 160 mg plus hydrochlorothiazide and in 84.8% starting valsartan 320 mg plus hydrochlorothiazide, without any additional titrations.18 Among patients with uncontrolled hypertension on monotherapy in the Irbesartan/HCTZ Blood Pressure Reductions in Diverse Patient Populations (INCLUSIVE) trial, use of a combination angiotensin receptor blocker/thiazide diuretic with a single dose titration resulted in overall control rates of 69% in 18 weeks; control rates were considerably higher in the 70% of the study population without diabetes and its stricter definition of blood pressure control.19 In the Avoiding Cardiovascular Events in Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, a comparison of the two drug combinations benazepril plus hydrochlorothiazide and benazepril plus amlodipine, with dose increases of the study medications after 1 and 2 months of therapy, control rates in excess of 70% were achieved by 3 months.14 With additional medication increases after 3 months, control rates in the US cohort in ACCOMPLISH reached 78% by 6 months. Common to these newer trials is the initiation of therapy with two antihypertensive drugs and mandated dose increases if control is not achieved within several weeks. The need for initial combination therapy is particularly important for grade 2 hypertension and in patients with diabetes and chronic renal disease, with its lower target goal of <130/80 mm Hg.1 Even with combination therapy, achieving blood pressure control in 3 months or less may be difficult. It will require multiple visits, as often as every 2 weeks, in order to monitor blood pressure and the impact of therapy intensification. This becomes practical and safe as forced titration experience, such as the irbesartan/thiazide combination studies to rapidly control severe and moderate hypertension, have shown that approximately 60% of the blood pressure reduction can be obtained within 2 weeks of initiating therapy.12, 13 Care for hypertensive patients will need to be changed to meet this expectation. Along with the broader use of combinations, physician practices will need to be organized so as to allow the rescheduling of hypertensive patients on intervals as short as 2 weeks. Home self-measurement of blood pressure will be especially useful for assessing responses to antihypertensive medications, improving patient adherence, and helping to diagnose white-coat effects and masked hypertension20, 21; the former requires restraint in medicating and the latter perhaps more aggressive therapy than indicated by office blood pressure readings.22, 23 A home blood pressure monitor with a graphic display of weekly control rates was associated in one study with more rapid blood pressure control than a standard monitor.24 An explicit expectation for blood pressure control within 3 months could have a number of beneficial effects on hypertensive patients. It would likely lead to more rapid and better blood pressure control with resulting reductions in cardiovascular morbidity and mortality. Achieving blood pressure control earlier may reduce the overall need for frequent office visits later, and hence, reduce overall costs. Such an expectation is easily measurable and could be readily incorporated into a national performance measure. Quality improvement efforts focusing on this measure would promote further improvements in care through the audit and feedback of clinicians’ practices. However, there also could be detrimental effects. Patients with hypertension could be overmedicated, although home blood pressure monitoring might minimize this problem. Inclusion as a quality measure may be associated with unintended consequences such as the diversion of resources away from other important aspects of care.25 Holding clinicians accountable to a 3-month threshold could also penalize clinicians providing excellent care to very difficult to control patients.26 Groups developing national quality measures will need to carefully balance the benefits and risks of incorporating this expectation into formal measures. We believe that the balance of the evidence supports changing the paradigm of hypertension treatment and implementing an expectation that blood pressure control will be achieved within 3 months of starting medication therapy. Such an explicit expectation would help guide clinicians and provide a benchmark for which they could strive. Start low, go slow should no longer serve as the model guiding drug therapy of hypertension. To maximize reductions in cardiovascular events, care for patients with severe or complicated hypertension should, right from the start, anticipate the more forceful and frequent interventions now supported by clinical trial evidence. Move fast, take control should now guide clinicians’ management of hypertension. Dr Berlowitz has received past grant support from Bristol-Myers-Squibb and Sanofi-Aventis; he has been a past consultant to Bristol-Myers-Squibb. Dr Franklin is a consultant for AtCor Medical and Bristol-Myers-Squibb.