III. Choice of therapy for adults with hypertension without compelling indications for specific agents

Prevention and Treatment

Subgroup Members: George K. Dresser, MD, PhD; Robert J. Herman, MD; Pavel Hamet, MD, PhD; Ellen Burgess, MD; Richard Lewanczuk, MD, PhD; Jean C. Gregoire, MD; Luc Poirier, BPharm, MSc
Central Review Committee: Doreen M. Rabi, MD, MSc; Stella S. Daskalopoulou, MD, PhD; Kaberi Dasgupta, MD, MSc; Kelly B. Zarnke, MD, MSc; Kara Nerenberg, MD, MSc; Kerry McBrien, MD, MPH; Kevin C. Harris, MD, MHSc; Alexander A. Leung, MD, MPH
Chair: Raj Padwal, MD, MSc

This information is based on the Hypertension Canada guidelines published in Leung, Alexander A. et al. Hypertension Canada’s 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. Can J Cardiol 2016; 32(5): 569-588.

Recommendations

  1. Recommendations for individuals with diastolic and/or systolic hypertension
    1. Initial therapy should be a single-agent thiazide/thiazide-like diuretic (Grade A), a β-blocker (in patients younger than 60 years; Grade B), an ACE inhibitor (in non-black patients; Grade B), a long-acting calcium channel blocker (CCB) (Grade B), or an ARB (Grade B). If there are adverse effects, another drug from this group should be substituted. Hypokalemia should be avoided in patients treated with thiazide/thiazide-like diuretic monotherapy (Grade C).
    2. Additional antihypertensive drugs should be used if target BP levels are not achieved with standard-dose monotherapy (Grade B). Add-on drugs should be chosen from first-line choices. Useful choices include a thiazide/thiazide-like diuretic or calcium-channel blocker (CCB) with either: Angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB) or β-blocker (Grade B for the combination of thiazide/thiazide-like diuretic and a dihydropyridine CCB; Grade C for the combination of dihydropyridine CCB and ACE inhibitor; and Grade D for all other combinations). Caution should be exercised in combining a nondihydropyridine CCB and a β-blocker (Grade D). The combination of an ACE inhibitor and an ARB is not recommended (Grade A).
    3. Combination therapy using two first-line agents might also be considered as initial treatment of hypertension (Grade C) if SBP is 20 mm Hg greater than target or if DBP is 10 mm Hg greater than target. However, caution should be exercised in patients in whom a decrease in BP from initial combination therapy is more likely to occur or in whom it would be poorly tolerated (e.g., elderly patients).
    4. If BP is still not controlled with a combination of 2 or more first-line agents, or there are adverse effects, other antihypertensive drugs may be added (Grade D).
    5. Possible reasons for poor response to therapy (Supplemental Table S10) should be considered (Grade D).
    6. Alpha(α)-blockers are not recommended as first-line agents for uncomplicated hypertension (Grade A); beta(β)-blockers are not recommended as first-line therapy for uncomplicated hypertension in patients 60 years of age or older (Grade A); and ACE inhibitors are not recommended as first-line therapy for uncomplicated hypertension in Black Canadian patients (Grade A). However, these agents may be used in patients with certain comorbid conditions or in combination therapy.
  2. Recommendations for individuals with isolated systolic hypertension
    1. Initial therapy should be single-agent therapy with a thiazide/thiazide-like diuretic (Grade A), a long-acting dihydropyridine CCB (Grade A), or an ARB (Grade B). If there are adverse effects, another drug from this group should be substituted. Hypokalemia should be avoided in patients treated with thiazide/thiazide-like diuretic monotherapy (Grade C).
    2. Additional antihypertensive drugs should be used if target BP levels are not achieved with standard-dose monotherapy (Grade B). Add-on drugs should be chosen from first-line options (Grade D).
    3. If BP is still not controlled with a combination of two or more first-line agents, or if there are adverse effects, other classes of drugs (such as α-blockers, ACE inhibitors, centrally acting agents, or nondihydropyridine CCBs) may be added or substituted (Grade D).
    4. Possible reasons for poor response to therapy (Supplemental Table S10) should be considered (Grade D).
    5. Alpha(α)-blockers are not recommended as first-line agents for uncomplicated isolated systolic hypertension (Grade A); and β-blockers are not recommended as first-line therapy for isolated systolic hypertension in patients aged ≥ 60 years (Grade A). However, both agents may be used in patients with certain comorbid conditions or in combination therapy.

Background

A. Recommendations for individuals with diastolic and/or systolic hypertension

1. Initial therapy should be a single-agent thiazide/thiazide-like diuretic (Grade A), a β-blocker (in patients younger than 60 years; Grade B), an ACE inhibitor (in non-black patients; Grade B), a long-acting calcium channel blocker (CCB) (Grade B); or an ARB (Grade B). If there are adverse effects, another drug from this group should be substituted. Hypokalemia should be avoided in patients treated with thiazide/thiazide-like diuretic monotherapy (Grade C).

‘Hypertension without compelling indications’ refers to patients with hypertension but without other identified comorbid conditions (such as diabetes mellitus or heart disease) that represent compelling indications for specific drug therapy. Randomized controlled trials have shown that antihypertensive therapy in these patients can reduce incidence of cardiovascular disease by 20% to 30%, depending on the specific outcome considered (1,2).

Reduction of hypertension-related complications continues to be paramount, and to depend more on the extent of blood pressure (BP) lowering than on choice of any specific drug class as first-line therapy for those patients without comorbid conditions which compel a specific drug class choice (such as diabetes mellitus, cardiac disease or renal disease) (6-9).

Therefore, in the choice of antihypertensive drugs, consideration of BP control effectiveness supersedes consideration of ‘pleiotropic’ effects of the five major antihypertensive classes.

Thiazides

There is strong evidence from meta-analyses of 16 placebo-controlled trials to indicate that thiazide diuretics, particularly at low doses (defined as < 50 mg/day hydrochlorothiazide), reduce stroke, myocardial infarction (MI), heart failure, and cardiovascular and all-cause mortality in patients with hypertension (Relative Risk Reduction [RRR], 25% to 30%) (24,25).

ALLHAT confirmed the central role of thiazide diuretics in first-line therapy of hypertension without compelling indications (Grade A evidence). This placebo-controlled, double-blind trial of 42,418 patients randomly assigned to chlorthalidone-, amlodipine-, lisinopril- or doxazosin-based regimens found no differences between the four arms in the primary outcome (fatal coronary artery disease or nonfatal myocardial infarction [MI]) or in all-cause mortality (26,27).

However, the chlorthalidone group had a statistically significant lower incidence of stroke than the doxazosin- and lisinopril-treated patients. The incidence of heart failure was also lower in chlorthalidone-treated patients than in the other three treatment arms. Further, a meta-analysis of 192,478 patients (from 42 clinical trials, including ALLHAT) (28), found that low-dose thiazide diuretics were as good as, and for some secondary endpoints, better than β-blockers, ACE inhibitors, CCBs or ARBs.

However, a meta-regression analysis across 15 randomized trials (120,574 patients) demonstrated that differences in outcomes between agents in active-control trials could be explained by differences in achieved systolic blood pressures (6). This meta-regression underscores the importance of blood pressure (BP) lowering to reduce cardiovascular risk.

The starting dose of hydrochlorothiazide or chlorthalidone should remain at 12.5 mg to 25 mg daily. This recommended dose largely based on a meta-analysis that reported greater benefits with low doses compared with high doses of thiazides in preventing cardiovascular events (25), and on studies reporting increased risks of metabolic side effects (dyslipidemia, hyperglycemia and hypokalemia) with higher-dose thiazides (29,30).

Indirect evidence exists that supports the use of chlorthalidone over hydrochlorothiazide (31). Chlorthalidone has consistently reduced cardiovascular events whereas the data examining hydrochlorothiazide is mixed.  Use of indapamide is also supported by high quality evidence (32-34). The NICE guidelines in the UK (https://www.nice.org.uk/guidance/cg127) have, based on these data, recommended use of chlorthalidone and indapamide preferential to hydrochlorothiazide.  Given the absence of head-to-head-trials, CHEP has not introduced a similar recommendation.

β-blockers

A recently published meta-analysis of 13 randomized controlled trials (n=105,951) (35) comparing β-blockers with other antihypertensive agents reported an increased risk of stroke with the use of β-blockers (Risk Reduction [RR] increase of 16%; 95%Confidence Interval [CI], 4% to 30%). However, this pooled end point was heterogeneous and largely driven by studies where the mean age of trial patients was > 60 years. When this analysis was restricted to trials where the mean age was < 60 years, this risk difference disappeared (36).

Furthermore, there were no differences in rates of myocardial infarction (MI) or deaths between β-blockers and other antihypertensives. Thus, we continue to recommend that β-blockers should not be used as first-line monotherapy in patients aged 60 years or older, but may be used in patients younger than 60 years of age. Evidence supporting use of beta-adrenergic antagonists (β-blockers) in this age group consists of four trials including the placebo-controlled Medical Research Council on Mild Hypertension trial (37), comparing thiazides with β-blockers, which failed cumulatively to detect any significant difference in occurrence of cardiovascular endpoints (RR, 0.95; 95%CI, 0.82 to 1.11), although number of events in these trials was insufficient to prove equivalence, thus justifying a Grade B rating (24).

Additionally, β-blockers may be used in in those with other compelling indications for β-blockade (such as symptomatic coronary disease, recent MI or congestive heart failure), or in those requiring polytherapy to control their BP.

ACE inhibitors

Early evidence supporting use of ACE inhibitors consists of two trials comparing these agents with thiazides and/or β-blockers (7,28). Total stroke was significantly higher in the ACE inhibitor-treated arm of the Captopril Prevention Project (CAPPP) (12) (RR, 1.25; 95%CI, 1.01 to 1.55); however, major cardiovascular event rates were not significantly different in either trial ([RR, 1.05; 95%CI, 0.90 to 1.22 in the CAPPP] and [RR, 1.21; 95%CI, 0.89 to 1.63 in the United Kingdom Prospective Diabetes Study/Hypertension in Diabetes Study] (12,37)).  Subsequently, ALLHAT demonstrated the equivalence of major classes, including ACE inhibition, in terms of primary endpoint reduction (38). Additional evidence in high-risk patients demonstrates the benefits of ACE inhibition;

A meta-analysis of four trials in patients with atherosclerotic risk factors showed clear reductions in stroke (RR, 0.70; 95%CI, 0.57 to 0.85), MI (RR, 0.80; 95%CI, 0.72 to 0.89), cardiovascular death (RR, 0.74; 95%CI, 0.64 to 0.85) and all-cause mortality (RR, 0.84; 95%CI, 0.76 to 0.94) with these agents (observed effect sizes were similar in patients with and without hypertension) (39–43).  Although some subjects with blood pressure levels in the normal range were included, the observed benefits are widely felt to be due to blood pressure reduction.

Calcium channel blockers

Evidence in support of long-acting dihydropyridine CCBs includes two placebo-controlled trials showing reductions in stroke (combined RR, 0.61; 95%CI, 0.44 to 0.85), major cardiovascular events (RR, 0.72; 95%CI, 0.59 to 0.87) and cardiovascular mortality (RR, 0.72; 95%CI, 0.52 to 0.98) with these agents. However, because neither trial enrolled young patients with uncomplicated hypertension—the Systolic Hypertension in Europe (SYST-EUR) trial was a trial of nitrendipine in elderly patients with isolated systolic hypertension, and the Prospective, Randomized Evaluation of the Vascular Effects of Norvasc (PREVENT) trial was a trial of amlodipine in patients with angiographically documented coronary artery disease, the majority of whom did not have hypertension—the recommendation is only a Grade B (39,44,45).

This Grade B recommendation for CCBs is based on an accumulation of trial data. In the NORDIL study (46), a randomized trial comparing diltiazem with diuretics and/or β-blocker therapy in 10,881 individuals with hypertension, there was no difference in the primary composite outcome of MI, stroke or cardiovascular death between diltiazem- and diuretic-treated patients. The CONVINCE study (47) randomly assigned 16,602 individuals with hypertension and one other risk factor to verapamil or control (atenolol or hydrochlorothiazide). There was no difference in the rate of occurrence of stroke, MI or cardiovascular death between verapamil and control.

Meta-analyses permitted an evaluation of the NORDIL and CONVINCE studies within the context of all studies of CCBs in hypertension. A meta-analysis of 42 clinical trials (192,478 patients) compared 14 nondihydropyridine and dihydropyridine CCB studies with low-dose diuretic studies (28). This meta-analysis, which included findings from the NORDIL and CONVINCE studies, found no difference in all-cause mortality or cardiovascular mortality between CCBs and low-dose thiazide diuretics.

Another meta-analysis (48) of 13 randomized trials evaluating incidence of stroke in 103,793 patients reported that CCB use was associated with a reduced risk of stroke compared with other antihypertensive drugs (odds ratio [OR], 0.90; 95%CI, 0.84 to 0.96), with a trend toward a reduced risk of stroke among nondihydropyridine CCB compared with other antihypertensive agents (OR 0.92; 95% CI 0.81 to 1.04). The totality of this evidence was believed to justify adding long-acting nondihydropyridine CCBs as one of the options for first-line therapy in patients with diastolic hypertension with or without systolic hypertension.  The results of the ALLHAT Trial also supports this recommendation (49).

Further support arises from three trials comparing long-acting dihydropyridine and thiazides, and/or β-blockers, which suggested equivalence (RR for major cardiovascular events, 1.01; 95%CI, 0.92 to 1.10, with excess risk of coronary events [RR, 1.12; 95%CI, 1.00 to 1.26] balanced by reduced risk of stroke [RR, 0.87; 95%CI, 0.77 to 0.98]) (22,39,51,52).

ARBs

Extrapolation from the LIFE trial (53) led to a new Grade B recommendation that ARBs were also appropriate first-line therapy for patients with hypertension without compelling indications for other agents. The LIFE trial compared the effect of losartan with atenolol in 9193 patients aged > 55 years, with electrocardiogram (ECG)-diagnosed left ventricular hypertrophy (LVH) and hypertension. This study found a significant reduction in the composite endpoint of death, MI or stroke favouring losartan (Risk Reduction [RR] 0.87; 95%Confidence Interval [CI], 0.77 to 0.98), even after accounting for differences in trial blood pressures.

The Evidence-Based Recommendations Task Force thought it appropriate to extrapolate from the LVH population enrolled in the LIFE trial to patients with uncomplicated hypertension, because patients with LVH constituted a substantial portion of trial participants in prior hypertension trials (and indeed, were the group in whom majority of events in earlier trials occurred).

It should be noted that LIFE used a control regimen with suboptimal efficacy in older patients with hypertension (i.e., β-blockers) (54).  However, data from the ONTARGET Trial supports the equivalence of ARBs to ACE inhibitors in high-risk patients and is the basis of the caution not to combine ACE and ARB therapy given the unfavourable risk benefit profile demonstrated (55).

Alpha-blockers

Alpha-blockers were inferior to diuretics in the ALLHAT trial and this resulted in early termination of the alpha-blocker arm of ALLHAT (56). Alpha-blockers can be considered if add-on therapy is necessary in resistant hypertension but are not indicated as a first line drug class.

Additional Comment

Experienced clinicians are well aware that most people with hypertension do not achieve sufficient BP control with the first agent chosen, and that a change of drug or addition of another agent may be necessary to achieve BP targets. Indeed, the average BP lowering achieved with a single drug is about 10 mm Hg/5 mm Hg respectively, and almost two-thirds of patients in recent antihypertensive trials required multiple agents to achieve BP pressure targets (68).

2. Additional antihypertensive drugs should be used if target BP levels are not achieved with standard-dose monotherapy (Grade B). Add-on drugs should be chosen from first-line choices. Useful choices include a thiazide/thiazide-like diuretic or calcium-channel blocker (CCB) with either: Angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB) or β-blocker (Grade B for the combination of thiazide/thiazide-like diuretic and a dihydropyridine CCB; Grade C for the combination of dihydropyridine CCB and ACE inhibitor; and Grade D for all other combinations). Caution should be exercised in combining a nondihydropyridine CCB and a β-blocker (Grade D). The combination of an ACE inhibitor and an ARB is not recommended (Grade A).

Antihypertensive drug therapy leads to reductions in cardiovascular morbidity and mortality (6,13). To achieve these substantial cardiovascular benefits, patients often require multiple antihypertensive agents. In recognition of the need for multidrug therapy, combination and add-on therapy trials are emerging. For example, at the end of the 5-year follow-up in ALLHAT, 63% of patients required at least two antihypertensive agents (26,27). Also, evidence supports the recommendation that combination therapy should be used if there is only a partial response to standard-dose monotherapy (Grade B). In a meta-analysis of 50 placebo-controlled trials testing drugs of two different categories separately and in combination, reductions in BP with combination drug therapy were additive, whereas adverse effects were less than additive (71). On the basis of their complementary physiological effects, rational choices for drug combinations include an ACE inhibitor, a β-blocker or an ARB combined with either a thiazide or a CCB (72,73).

Based on results of the FEVER Trial (74), a combination comprising a thiazide diuretic with a dihydropyridine CCB is recommended for patients who have not achieved target BP with antihypertensive monotherapy. In this study, 9,711 hypertensive patients (from China), aged 50 to 79 years, with either established cardiovascular disease or two cardiovascular risk factors, were initiated on low-dose hydrochlorothiazide (HCTZ) after a washout of all previous agents. Patients were subsequently randomly assigned to additional low-dose felodipine or to placebo, with the option of further open-label antihypertensive agents to maintain a BP lower than 160/95 mm Hg. Those patients assigned randomly to felodipine plus HCTZ had lower BP (138.1/82.3 mm Hg), compared with those patients assigned placebo plus HCTZ (141.1/83.9 mm Hg), and a significantly lower risk of fatal or nonfatal stroke (hazard ratio [HR] 0.73; 95%CI, 0.60 to 0.89) after a mean follow-up period of 3.3 years. Although it was unclear whether imaging was used to ascertain the primary outcome of stroke, a consistent benefit was shown favouring felodipine plus HCTZ for secondary endpoints, including cardiovascular events (HR 0.73; 95%CI, 0.61 to 0.86) and total mortality (HR 0.69; 95%CI, 0.54 to 0.89).

These results, demonstrating efficacy of a dihydropyridine CCB and diuretic combination, are consistent with findings from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial (18,75). In this trial, 15,245 hypertensive patients, older than 50 years of age, with cardiovascular disease or with cardiovascular risk factors, were randomly assigned to a valsartan- or to an amlodipine-based regimen. Amlodipine and valsartan treatment groups were given with HCTZ as the first-step add-on drug to achieve target BP (25% of the amlodipine group received HCTZ in combination). Overall, there was no difference in the primary outcome of cardiac morbidity and mortality (HR 1.03; 95%CI, 0.94 to 1.14) between amlodipine- and valsartan-based regimens.

The CWG upgraded the recommendation for combination of a dihydropyridine CCB with an ACE inhibitor to Grade C based on results of the ASCOT-BPLA trial (76). In the ASCOT-BPLA trial, 19,257 hypertensive patients, aged 40 to 79 years, and at least three other cardiac risk factors were randomly assigned to amlodipine (with addition of perindopril as required to achieve target BPs) versus atenolol (adding a thiazide diuretic as required). Overall, 50% of patients in the amlodipine arm and 55% of patients in the atenolol arm received combination therapy. Of these combination therapy arms, patients assigned to amlodipine/perindopril had greater BP lowering compared with those patients assigned to atenolol/thiazide. In fact, the trial was terminated early because the amlodipine/perindopril group had a significantly lower mortality (Risk Ratio [RR], 0.89; 95%CI, 0.81 to 0.99) and a reduction in other secondary endpoints such as stroke and cardiovascular death compared with the atenolol/thiazide group.

A Grade A recommendation to avoid dual RAAS blockade with ACE inhibitor and ARB therapy was added based on evidence of harm from the ONTARGET study (77,78). The ONTARGET study was a large, randomized, double-blind trial comparing effects of ACE inhibitor ramipril 10 mg/day and ARB telmisartan 80 mg/day, separately and in combination, in patients who were at least 55 years of age and who had established vascular disease or diabetes with organ damage. Among the 25,620 patients randomized, and after a median follow-up period of 56 months, the telmisartan (-0.9/-0.6 mm Hg) and the combination therapy groups (-2.4/-1.4 mm Hg) had significantly lower BPs than the ramipril monotherapy group.

There was no significant difference in the primary outcome (cardiovascular death, myocardial infarction, stroke or hospitalization for congestive heart failure) between the ramipril and telmisartan monotherapy groups or the combination therapy group compared with the ramipril monotherapy group. However, combination therapy was associated with significantly higher rates of discontinuation due to syncope (0.3% versus 0.2%) and renal impairment (13.5% versus 10.2%) compared with ramipril. From the pre-specified secondary endpoint analysis (78), combination therapy was associated with a significantly increased risk of dialysis, with doubling of serum creatinine or with death compared with ramipril monotherapy (hazard ratio [HR], 1.09; 95%CI, 1.01–1.18; P=0.037).

The findings of this high-quality trial demonstrate combining full doses of telmisartan and ramipril does not provide additional cardiovascular benefits compared with monotherapy with either agent alone, but combining does significantly increase the adverse event rate. It is unclear whether less than full doses of these agents in combination cause worsening renal impairment or hypotension. However, randomized trials of patients with heart failure also report an increased rate of adverse events from renal impairment with combination ACE inhibitor and ARB at various dosages (79,80).

3. Combination therapy using two first-line agents might also be considered as initial treatment of hypertension (Grade C) if SBP is 20 mm Hg greater than target or if DBP is 10 mm Hg greater than target. However, caution should be exercised in patients in whom a decrease in BP from initial combination therapy is more likely to occur or in whom it would be poorly tolerated (e.g., elderly patients).

The majority of antihypertensive drug trials were based on step-up titration schemes, in which a single agent was initiated and in which doses were titrated upward or other antihypertensive agents were added until target BP was achieved. These studies form the foundation for the Grades A and B monotherapy recommendations, and represent the primary strategy for initiating antihypertensive drug therapy.

However, because many patients require more than one drug to achieve blood pressure targets, some trials have examined the safety and efficacy of initial combination therapy on reduction of cardiovascular endpoints. On review of these trials, CHEP Recommendations include a Grade C recommendation supporting combination therapy for initial treatment.

In the FEVER trial (83), 9711 hypertensive patients from China 50 to 79 years of age were initiated on low-dose hydrochlorothiazide and then randomly assigned to additional low-dose felodipine or placebo. After a mean follow-up of 3.3 years, those assigned to combination felodipine plus hydrochlorothiazide had lower BP and a significantly lower risk of fatal or nonfatal stroke (HR 0.73; 95%CI, 0.60 to 0.89), cardiovascular events (HR 0.73; 95%CI, 0.61 to 0.86) and total mortality (HR 0.69; 95%CI, 0.54 to 0.89). In addition, the PROGRESS trial (84) demonstrated a greater BP-lowering effect and a significant reduction in stroke incidence (RR 0.57; 95%CI, 0.46 to 0.70; P<0.001) in patients allocated to combination therapy (indapamide plus perindopril) compared with placebo among 6,105 patients with a history of stroke or transient ischemic attack. However, single drug therapy was not associated with a reduction in stroke.

The results from PROGRESS need to be interpreted with caution because allocation to combination therapy compared with monotherapy was determined by the physician rather than through random assignment. In the BP-lowering arm of the ADVANCE Trial (85), 11,140 patients aged 55 years or older, with type 2 diabetes and with a history of major vascular disease or vascular risk factors were randomly assigned to perindopril plus indapamide versus placebo, in addition to their current antihypertensive therapy. After a mean follow-up of 4.3 years, combination therapy was associated with a 5.6/2.2 mm Hg greater reduction in BP compared with placebo. Yet there were no significant differences in the macrovascular or microvascular primary endpoints between combination therapy and placebo. In the secondary endpoint analysis, however, combination therapy was associated with a significant reduction in cardiovascular death (HR 0.82; 95%CI, 0.68 to 0.98; P=0.03) and total mortality (HR 0.86; 95%CI, 0.75 to 0.98; P=0.03) compared with placebo. This study was given a Grade C rating because the benefits of combination therapy were largely found in the secondary endpoint evaluation, where multiple secondary endpoints were tested, and because of the need to extrapolate from a diabetic population (85).

Despite the limitations of these studies, the findings support collectively a greater BP-lowering effect with combination therapy compared with monotherapy, and a reduction in cardiovascular endpoints. Therefore, given the significantly greater BP reductions associated with combination therapy, a proviso was added that a combination of two first-line agents should be used in patients with a significant elevation in BP, and that caution should be exercised in patients in whom a substantial fall in BP is more likely to occur or is more poorly tolerated (e.g., elderly patients).

4. If BP is still not controlled with a combination of 2 or more first-line agents, or there are adverse effects, other antihypertensive drugs may be added (Grade D).

This expert consensus recommendation is based on the fact that the majority of antihypertensive drug trials were based on step-up titration schemes, in which a single agent was initiated and in which doses were titrated upward or other antihypertensive agents were added until target BP was achieved.

5. Possible reasons for poor response to therapy (Supplemental Table S10) should be considered (Grade D).

This is an expert consensus recommendation.

6. Alpha(α)-blockers are not recommended as first-line agents for uncomplicated hypertension (Grade A); beta(β)-blockers are not recommended as first-line therapy for uncomplicated hypertension in patients 60 years of age or older (Grade A); and ACE inhibitors are not recommended as first-line therapy for uncomplicated hypertension in Black Canadian patients (Grade A). However, these agents may be used in patients with certain comorbid conditions or in combination therapy.

Alpha-blockers were inferior to diuretics in the ALLHAT trial and this resulted in early termination of the alpha-blocker arm of ALLHAT (88). Alpha-blockers can be considered if add-on therapy is necessary in resistant hypertension but are not indicated as a first line drug class.

A recently published meta-analysis of 13 randomized controlled trials (n=105,951) (36) comparing β-blockers with other antihypertensive agents reported an increased risk of stroke with the use of β-blockers (RR 16%↑; 95%CI, 4% to 30%). However, this pooled endpoint was heterogeneous and was driven largely by studies where the mean age of trial patients was > 60 years. When this analysis was restricted to trials where the mean age was < 60 years, this risk difference disappeared (37).

Furthermore, there were no differences in rates of myocardial infarction (MI) or deaths between β-blockers and other antihypertensives. Thus, CHEP Recommendations continue to state that β-blockers should not be used as first-line monotherapy in patients aged 60 years or older, but may be used in patients younger than 60 years of age, or in those with other compelling indications for β-blockade (such as symptomatic coronary disease, recent MI or congestive heart failure), or in those requiring polytherapy to control their BP.

Additionally, the CHEP recommends ACE inhibitors be used with caution as first-line monotherapy in Black Canadian patients, based on an a priori subgroup analysis from ALLHAT, in which rates of stroke (RR 1.40; 95%CI, 1.17 to 1.68) and combined cardiovascular disease (RR 1.19; 95% CI 1.09 to 1.30) were significantly higher in African-American patients treated with an ACE inhibitor than in those African-American patients treated with a thiazide (26,27). These rates echo results of a post hoc analysis of the Studies of Left Ventricular Dysfunction (SOLVD) Trial in which African-American patients with left ventricular systolic dysfunction did not appear to derive any antihypertensive (or mortality) benefit from ACE inhibitor therapy versus placebo (86).

However, the use of β-blockers in the elderly, ACE inhibitors in Black Canadian patients, or α-blockers may be appropriate in selected hypertensive patients with concomitant conditions or in combination therapy.

B. Recommendations for individuals with isolated systolic hypertension

1. Initial therapy should be single-agent therapy with a thiazide/thiazide-like diuretic (Grade A), a long-acting dihydropyridine CCB (Grade A), or an ARB (Grade B). If there are adverse effects, another drug from this group should be substituted. Hypokalemia should be avoided in patients treated with thiazide/thiazide-like diuretic monotherapy (Grade C).

Failure to treat isolated systolic hypertension in the elderly represents an important gap in health care, since hypertension is more prevalent in the elderly. Furthermore, treatment of isolated systolic hypertension in the elderly is much more effective (i.e., number needed to treat is much smaller) than treating diastolic hypertension in younger patients: Stroke is reduced by half and MI by 40% (56). Systolic BP continues to rise with age, whereas diastolic BP levels off at age 55 years and then declines with age. Furthermore, vascular complications correlate more strongly with systolic than with diastolic blood pressure (10,58).

The basis of recommendations for therapy in older hypertensive patients comes chiefly from large, well-conducted, randomized controlled trials (45,56,57,59–67,89).

These studies included relatively healthy elderly people. Thus, generalizability of recommendations to frail elderly is limited. (For newly diagnosed hypertension in patients older than 84 years, investigation and therapy should be cautious and be individualized.) As in younger patients, recommendations for preferred therapies were based on consideration of those drugs that have been shown (in level I studies) to reduce both BP and BP-related complications. This reduction is most clearly demonstrated with thiazide diuretics (59) and with longer-acting DHP CCBs (45).

Thiazides (age > 60 years)

As outlined above for adults aged < 60 years, there is strong, placebo-controlled, clinical trial evidence showing reductions in stroke, MI, heart failure, and in cardiovascular and all-cause mortality with thiazide diuretics (particularly at low doses), in both younger and older patients with hypertension (24,25).

CCBs (age > 60 years)

The recommendation backing the use of long-acting dihydropyridine CCBs is supported by the placebo-controlled SYST-EUR trial, which showed statistically significant reductions in stroke (RR, 0.59; 95%CI, 0.41 to 0.83), and strong trends in MI (RR, 0.76; 95%CI, 0.54 to 1.06), in heart failure (RR, 0.75; 95%CI, 0.50 to 1.13) and in cardiovascular death (RR, 0.75; 95%CI, 0.54 to 1.03), consistent with those reductions seen in the thiazide trials (45). These data are consistent with apparent equivalence in cardiovascular outcome rates between those patients treated with long-acting DHPs and those patients treated with thiazides in the International Nifedipine once daily Study, Intervention as a Goal in Hypertension Treatment trial (INSIGHT) (50).

ARBs (age > 60 years)

The evidence supporting the use of ARBs in this age group is derived chiefly from the aforementioned LIFE trial.(53)

2. Additional antihypertensive drugs should be used if target BP levels are not achieved with standard-dose monotherapy (Grade B). Add-on drugs should be chosen from first-line options (Grade D).

Add-on agents should be chosen from first-line options because there is evidence supporting the use of these agents to reduce cardiovascular morbidity and/or mortality as summarized above.

4. Possible reasons for poor response to therapy (Supplemental Table S10) should be considered (Grade D).

This is an expert consensus recommendation.

5. Alpha(α)-blockers are not recommended as first-line agents for uncomplicated isolated systolic hypertension (Grade A); and β-blockers are not recommended as first-line therapy for isolated systolic hypertension in patients aged ≥ 60 years (Grade A). However, both agents may be used in patients with certain comorbid conditions or in combination therapy.

Please see similar recommendation above for background and rationale.

References

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