Grade 1 hypertension: to treat or not to treat?



by C. Thomopoulos, Greece

Costas THOMOPOULOS
MD, MSc, PhD, FESC
Department of Cardiology
Helena Venizelou Hospital
Athens, GREECE




Untreated hypertensive patients are usually stratified in hypertension grades (stages) according to systolic and diastolic blood pressure (BP) to guide therapeutic decisions. Old placebo-controlled randomized trials focused on so-called “mild hypertension,” but its definition nowadays is problematic and different to that of grade (stage) 1 hypertension, endorsed by hypertension societies worldwide. There has been much scientific debate on whether or not it is beneficial to treat grade 1 hypertensive patients. However, recent meta-analyses using different designs (individual versus tabular data) and approaches (selection of trials with untreated patients; restricting analyses in low/moderate risk; stratifying hypertension grade by using both systolic and diastolic BP) have provided evidence that grade 1 hypertension should be treated, except in special cases. Early treatment of hypertension is further supported by the notion that any delay, whether due to clinical inertia or not, significantly increases cardiovascular events. Indeed, aging and ongoing adverse cardiovascular adaptations in untreated hypertension heighten both the individual cardiovascular risk and the residual risk of treated patients, years after the initial diagnosis. The clinical approach to office grade 1 hypertension in untreated patients should be directed toward the confirmation of BP levels with out-of-clinic measurements and also toward taking into account the age and overall health of patients. On top of lifestyle changes, single-drug antihypertensive treatment to reach and remain within BP target can initially be implemented. In cases of failure to achieve the desirable BP level, fixed-dose combinations containing low doses of each component agent might be an option to pursue. However, special attention should be paid to the tolerability of each selected drug, especially in the elderly.

Grade 1 hypertension versus “mild hypertension”

According to the European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines on the management of arterial hypertension, grade 1 hypertension defines the category of hypertension with systolic blood pressure (SBP) levels between 140 mm Hg and 159 mm Hg and/or diastolic blood pressure (DBP) levels between 90 and 99 mm Hg.1 The same thresholds have been endorsed in the seventh report of the Joint National Committee to define stage 1 hypertension.2 Grade or stage 1 hypertension is not synonymous with “mild hypertension” because the latter term was used some decades before to define different “mild” increases in DBP without paying attention to baseline SBP levels.3


Table I.
Evidence
on risk reduction
from
meta-analyses
in grade 1
hypertension.
Abbreviations:
BPLTTC, Blood
Pressure Lowering
Treatment
Trialists’ Collaboration;
CV, cardiovascular;
HF, heart failure;
MI, myocardial
infarction.




“Mild hypertension” trials were performed before 1993 and examined the effect of blood pressure lowering on various outcomes in patients at low cardiovascular risk, judged by DBP levels only. However, patients enrolled in “mild hypertension” trials were not always at low risk and, in addition, their SBP and DBP were in most cases well above current thresholds that define grade 1 hypertension. Due to the misleading clinical qualification of “mild” alongside “hypertension,” the principal clinical question is whether or not we should pharmacologically treat patients with grade 1 hypertension, especially those at low/moderate total cardiovascular risk.

The evidence so far…

It should be acknowledged that the evidence so far in the treatment of grade 1 hypertension is weak because the majority of blood pressure–lowering trials were performed in patients with baseline SBP ≥160 mm Hg and because patients whose SBP at randomization was between 140 and 159 mm Hg were already receiving antihypertensive treatment. Thus, the presumed qualification of grade 1 hypertension in most cases is largely apparent. Also, the results of trials performed before 1993 in the setting of so-called “mild hypertension” cannot be translated in the context of grade 1 hypertension for the reasons explained above. For want of robust evidence in the treatment of patients with grade 1 hypertension, different meta-analyses were performed to address whether blood pressure lowering in this particular setting was accompanied by treatment benefits on various outcomes (Table I).4-9





The analysis by Czernichow et al,4 which included a large number of trials in patients at different baseline SBP and DBP levels, indicated significant cardiovascular outcome reductions at all baseline blood pressure grades, including grade 1. However, this analysis considered patients who were already treated at baseline and thus the results cannot be extended to untreated grade 1 hypertension. The large meta-analysis by Law et al5 was also conducted in patients on treatment at the time of randomization, and risk reductions were calculated separately for SBP and DBP, whereas hypertension grade definition requires simultaneous consideration of both SBP and DBP to include trials that comply with the definition of grade 1 hypertension. Law et al5 included heart failure and postmyocardial infarction trials, which makes the applicability of the results in grade 1 hypertension at least disputable. The latter shortcomings were also detected in the meta-analysis by Thompson et al,6 who studied the effect of blood pressure lowering in patients with apparent (because of background treatment) normotension.


Figure 1. Effects of blood pressure lowering in trials of grade 1 hypertension.
Mean systolic and diastolic blood pressure at randomization was 152.8 mm Hg and 95 mm Hg, respectively, in grade 1 hypertensive patients (panel A); and 146
mm Hg and 91 mm Hg, respectively, in grade 1 hypertensive patients with low/moderate CV risk (panel B). Absolute risk estimates were calculated only for trials at
low/moderate risk (panel B) because the trials in panel A have different levels of baseline total cardiovascular risk. Data derived from Thomopoulos et al.9
Abbreviations: ARR, absolute risk reduction (number of events prevented for every 1000 patients treated for 5 years with a standardized RR); CHD, coronary heart
disease; CI, confidence interval; CV, cardiovascular; HF, heart failure; n, number; pts, patients; RR, Mantel-Haenszel risk ratios.
*CV death rate in the control group was 4.5% over 10 years.




The Cochrane Collaboration meta-analysis by Diao et al7 considered old “mild hypertension” trials. Individualized data from correctly defined grade 1 hypertensive patients were used. Although the analysis was largely underpowered (30 strokes; 122 coronary events; and 165 major cardiovascular events), they concluded that pharmacotherapy of grade 1 hypertension was unable to reduce outcomes, with stroke marginally lacking statistical significance (relative risk, 0.51; 95% confidence interval, 0.24 to 1.08).

The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC)8 enriched the previously reported Cochrane Collaboration7 by also using available individualized data from nine more trials after post hoc selection of patients with grade 1 hypertension. The BPLTTC meta-analysis, which included 15 266 patients with grade 1 hypertension, reported risk reductions in stroke, cardiovascular death, and all-cause death following blood pressure–lowering treatment. However, even here, background antihypertensive treatment at baseline was substantial, suggesting that some patients only had apparent grade 1 hypertension. Finally, this pool of patients had a significant level of overall cardiovascular risk (6.2% risk of cardiovascular death over ten years), and this result can hardly be applicable to patients with true grade 1 hypertension and low/moderate total cardiovascular risk.

The benefit on various cardiovascular outcomes after treatment initiation in patients with grade 1 hypertension has been demonstrated by Thomopoulos et al9 in a recent meta-analysis of 32 trials that included 104 359 patients categorized by average baseline blood pressure values into the three grades of hypertension. Grade 1 hypertension was represented by six trials and 16 036 participants. It was shown that blood pressure lowering reduced major cardiovascular events (fatal and nonfatal coronary heart disease and stroke), cardiovascular death, and all-cause death by 20%, 22%, and 18%, respectively. The benefit was not different to that observed following blood pressure lowering in untreated grade 2 and grade 3 hypertension (Figure 1A). The authors then restricted their analysis to patients with mild/moderate overall cardiovascular risk and reproduced the same results, except for the reduction in cardiovascular death (Figure 1B). In this latter analysis, which included 8975 patients with grade 1 hypertension and an overall cardiovascular risk <5%, the reduction in absolute risk was also noteworthy: blood pressure lowering prevented 21 strokes, 34 major cardiovascular events, and 19 deaths for every 1000 patients treated for five years (Figure 1B). These effects remained almost unchanged when the HOPE-3 (Heart Outcomes Prevention and Evaluation 3) trial, with its predefined upper blood pressure subgroup, was added in the analysis (unpublished data).

The evidence from grade 1 hypertension trials considered in all the meta-analyses was derived from office blood pressure measurements. Although ambulatory blood pressure monitoring may offer more precise measurements and exclude white-coat hypertension, its value has never been tested in large hypertension trials.

What do the current guidelines say?

The 2013 ESH/ESC guidelines on the management of arterial hypertension1 as well as the American and International Societies of Hypertension10 recommend drug treatment in low/ moderate risk grade 1 hypertension on top of previously prescribed lifestyle changes, when these latter measures alone fail to control blood pressure below 140/90 mm Hg for several weeks. The United Kingdom’s National Institute for Health and Care Excellence 2011 hypertension guidelines recommend restricting drug treatment only to those grade 1 hypertensive patients with high total cardiovascular risk or with evidence of target organ damage.11 These guidelines also recommend confirming grade 1 hypertension by ambulatory blood pressure monitoring. Members of the Eighth Joint National Committee report (JNC 8) suggest initiation of drug treatment in stage (grade) 1 hypertension based on “mild hypertension” trials and expert opinion for diastolic and systolic blood pressure components, respectively.12

A clinical approach

Apparent (on treatment) grade 1 hypertension
Figure 2 shows what might be a clinical approach to treatment of grade 1 hypertension. First, it has to be established whether or not the patient who presents to the clinician with blood pressure values in the range of grade 1 hypertension is already being treated. With patients on antihypertensive treatment, apparent grade 1 hypertension indicates that a higher grade of hypertension has remained uncontrolled. Lowering blood pressure below 140/90 mm Hg is beneficial, as demonstrated in large meta-analyses of trials including both primary and secondary prevention patients on antihypertensive treatment at the time of randomization.4-9 In previously treated elderly patients in overall good health presenting with apparent grade 1 hypertension, pursuing blood pressure lowering below 140/90 mm Hg might be desirable, and careful drug titration should be used to reach this target while avoiding drugrelated side effects.13 However, clinical decisions should be individualized, and special attention should be paid to establishing whether blood pressure lowering is well tolerated. In the very elderly (octogenarians), there is no evidence available for treatment initiation in grade 1 hypertension because the only available trial in this population, HYVET (HYpertension in the Very Elderly Trial),14 recruited fit patients with SBP ≥160 mm Hg. In this trial, SBP in the active group (on indapamide, alone or in combination with perindopril) reached 144.7 mm Hg, suggesting that octogenarians should not discontinue well-tolerated treatment.


Figure 2.
A clinical approach
to the
treatment of
grade 1 hypertension.
Abbreviations:
BP, blood pressure;
mm Hg, millimeter
of mercury.
*Variably defined
as >60, 65, and
70 years; †Expert
opinion; ‡10-year
cardiovascular
death rate (presence
of diabetes
mellitus, target
organ damage,
or chronic kidney
disease stage 3 or
more indicate total
cardiovascular risk
≥5%).




True (untreated) grade 1 hypertension
Untreated patients with grade 1 hypertension are younger (below 65 years of age) and have not had previous cardiovascular events (primary prevention). The prescription of lifestyle changes is mandatory, and drug treatment should be immediately initiated in those with target organ damage, chronic kidney disease with reduced glomerular filtration rate, or diabetes mellitus because these conditions suggest high total cardiovascular risk.1 In patients with low/moderate total cardiovascular risk, after the prescription of lifestyle changes the potential benefit of drug treatment has to be balanced against potential harm, according to the following considerations:

1. Reduction in the relative and absolute risks of major cardiovascular events, all-cause death, and cardiovascular death with blood pressure lowering in grade 1 hypertension has recently been shown in a meta-analysis by Thomopoulos et al,9 strengthening previous evidence from a meta-analysis by the BPLTTC.8 In the former meta-analysis,9 it was also shown that all grades of untreated hypertension (or hypertension for which minor treatment has been prescribed) benefit from blood pressure lowering, and that treatment initiation in low/ moderate risk grade 1 hypertension is favorable. Finally, the predefined grade 1 hypertension subgroup (baseline SBP 154 mm Hg) of the recently published HOPE-315 showed a 27% reduction in the risk of major cardiovascular events among patients at moderate cardiovascular risk, which translates into the prevention of one event for every 63 patients treated for five years.

2. The greatest benefit of blood pressure lowering is achieved in low/moderate risk patients because the higher the total cardiovascular risk, the higher the residual risk.16 Thus, treatment initiation at a lower hypertension grade in patients at low/moderate risk not only prevents cardiovascular events, but it is also accompanied by a reduction in treatment failure. Waiting for total cardiovascular risk to increase before treatment initiation might expose individuals to increased risk of cardiovascular events, development of target organ damage, and most importantly unmodifiable risk, because high risk once present is not always reversible.

3. Patients with grade 1 hypertension at low/moderate risk should be treated with one drug initially and possibly at a follow- up evaluation with two agents in combination (fixed) at smaller doses (eg, half standard dose) to reduce blood pressure below 140/90 mm Hg. The potential benefit of blood pressure lowering should outweigh the potential harm of drug related adverse events. Since the presentation of drug-related adverse events increases with the extent of blood pressure lowering, targeting to 130 to 140 mm Hg might minimize drug tolerance issues.13

4. Elderly patients (at least those younger than 80 years) with untreated grade 1 hypertension without a history of cardiovascular events should not be considered at low/moderate risk because older individuals are usually at high risk. In this particular case, blood pressure might be lowered below 140/ 90 mm Hg provided that treatment is well tolerated, but this decision is not evidence-based because trials in this population recruited patients with at least grade 2 hypertension.

5. Young individuals at low risk of isolated grade 1 systolic hypertension should not be treated by drug treatment and only lifestyle measures should be prescribed. Because of scanty data in this particular group, close follow-up is desirable.

Practical issues
In previously untreated patients with grade 1 hypertension, the decision about whether or not to initiate treatment depends on the overall clinical evaluation. First, blood pressure should be adequately measured at the office. It is also reasonable to assume that ambulatory blood pressure monitoring or home blood pressure measurements can help confirm the diagnosis. Evaluation of 10-year cardiovascular death risk is based on SCORE (Systematic COronary Risk Evaluation) criteria and rates ≥5% indicate high risk. The presence of diabetes, chronic kidney disease of stage 3 or more, or signs of target organ damage directly classify patients at high or very high risk. In some cases, patients at low/moderate risk may be prescribed lifestyle changes for several weeks before pharmacological treatment is initiated. When pharmacological treatment is finally prescribed, efforts to change lifestyle should not discontinue. Single-drug therapy at a standard dose should be introduced, and blood pressure control and tolerance evaluated at follow-up visits. A fixed-dose combination containing low doses of each active agent may provide an alternative to monotherapy if hypertension remains uncontrolled. In the elderly, cardiovascular risk is usually high, and initiation of treatment is indicated with grade 1 hypertension. However, particular attention should be paid to drug-related adverse events, and treatment escalation should be done carefully.

Conclusion

Grade 1 hypertension, with only some exceptions, should be treated pharmacologically on top of lifestyle changes even in those at low/moderate risk. Of late, the synthesis of evidence through meta-analysis has shown clear benefits in starting drug treatment early. This evidence is further supported by the notion that delaying the treatment of hypertension significantly increases cardiovascular events. Indeed, aging and ongoing adverse cardiovascular adaptations in untreated hypertension increase both the individual cardiovascular risk and the residual risk of patients treated, years after the initial diagnosis. n


References
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Keywords: grade 1 hypertension; total cardiovascular risk; mild hypertension; cardiovascular outcomes; guidelines