VI. Treatment of Hypertension in Association With Ischemic Heart Disease

Prevention and Treatment

Subgroup Members: Simon W. Rabkin, MD; Gordon W. Moe, MD, MSc; Jonathan G. Howlett, MD
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 hypertensive patients with CAD
    1. For most hypertensive patients with CAD, an ACE inhibitor or ARB is recommended (Grade A).
    2. For hypertensive patients with CAD, but without coexisting systolic heart failure, the combination of an ACE inhibitor and ARB is not recommended (Grade B).
    3. For high-risk hypertensive patients, when combination therapy is being used, choices should be individualized. The combination of an ACE inhibitor and a dihydropyridine CCB is preferable to an ACE inhibitor and a thiazide/thiazide-like diuretic in selected patients (Grade A).
    4. For patients with stable angina pectoris but without previous heart failure, myocardial infarction, or coronary artery bypass surgery, either a b-blocker or CCB can be used as initial therapy (Grade B; revised recommendation).
    5. Short-acting nifedipine should not be used (Grade D).
    6. When decreasing SBP to target levels in patients with established CAD (especially if isolated systolic hypertension is present), be cautious when the DBP is ≤ 60 mm Hg because of concerns that myocardial ischemia might be exacerbated (Grade D).
  2. Recommendations for patients with hypertension who have had a recent myocardial infarction (MI)
    1. Initial therapy should include a β-blocker and an ACE inhibitor (Grade A).
    2. An ARB can be used if the patient is intolerant of an ACE inhibitor (Grade A in patients with left ventricular (LV) systolic dysfunction).
    3. CCBs may be used in patients after MI when β-blockers are contraindicated or not effective. Nondihydropyridine (NDHP) CCBs should not be used when heart failure is present, evidenced by pulmonary congestion at time of examination or radiography (Grade D).

Background

A. Recommendations for hypertensive patients with CAD (CAD)

1. For most hypertensive patients with CAD, an ACE inhibitor or ARB is recommended (Grade A).

ACE inhibitors are recommended for moderate- to high-risk patients
with CAD. Various trials have evaluated treatment of hypertension in association with CAD, including the Heart Outcomes Prevention Evaluation (HOPE) and European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) studies (2,3). Meta-analyses of these and other trials demonstrate clinically important and statistically significant reductions in cardiovascular events and/or death with ACE inhibitor therapy (4).

CHEP recommendations also include (ARBs) as an option based on published randomized trials evaluating role of ARBs in patients with CAD and hypertension. ONTARGET (13) compared telmisartan 80 mg per day with ramipril 10 mg per day in 25,620 patients with vascular disease or diabetes with end-organ damage. Overall, 75% of patients had a history of coronary disease and 69% had a history of hypertension. The primary outcome was a composite of cardiovascular death, MI, stroke or hospitalization for heart failure. During a median follow-up of 56 months, the primary outcome occurred in 16.7% of patients in the telmisartan group and 16.5% of patients in the ramipril group (telmisartan vs. ramipril, RR, 1.01; 95%CI, 0.94 to 1.09). The mean BP throughout the study period was 0.9/0.6 mm Hg lower in patients treated with telmisartan than in those treated with ramipril. Adjustment for this small difference in blood pressure did not affect materially results for the primary outcome (RR, 1.02; 95%CI, 0.95 to 1.10). Total mortality (RR, 0.99; 95%CI, 0.91 to 1.07) and the composite of cardiovascular death, MI or stroke (RR 0.98; 95%CI, 0.90 to 1.07) were similar.

Two additional trials compared ARBs with placebo in high-risk patients (14,15). TRANSCEND (14) assigned 5926 patients intolerant to ACE inhibitors to receive telmisartan 80 mg per day or placebo, and outcomes were identical to those studied in ONTARGET (13). At baseline, 77% of patients had a history of hypertension and 75% of patients had CAD. Throughout the study, BP was lower in the telmisartan group than in the placebo group (mean difference between groups, 4.0/2.2 mm Hg). After a median follow-up period of 56 months, the primary outcome occurred in 15.7% of patients in the telmisartan group and 17.0% of patients in the placebo group (telmisartan versus placebo RR 0.92; 95%CI, 0.81 to 1.05). The composite of cardiovascular death, myocardial infarction or stroke occurred in 13.0% of patients in the telmisartan group and 14.8% of patients assigned to the placebo group (RR, 0.87; 95%CI, 0.76 to 1.00). Fewer patients in the telmisartan group (30.3%) were hospitalized for cardiovascular cause compared with the placebo group (33.0%; RR, 0.92; 95%CI, 0.85 to 0.99).

In a comparison similar to TRANSCEND, PRoFESS (15) assigned 20,332 patients with cerebrovascular disease (74% and 19% of whom had hypertension and extra cranial atherosclerosis, respectively) to telmisartan 80 mg per day or to placebo in a two-by-two (2×2) factorial comparison (other factor being assignment to clopidogrel or low-dose acetylsalicylic acid (ASA) in combination with extended-release dipyridamole). Throughout the study, mean BP was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. During a mean follow-up period of 2.5 years, primary outcome of first recurrent stroke occurred in 880 patients (8.7%) in the telmisartan group compared with 934 patients (9.2%) in the placebo group (RR, 0.95; 95%CI, 0.86 to 1.04). The secondary outcome of stroke, MI or death from cardiovascular causes occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (RR, 0.94; 95%CI, 0.87 to 1.01).

The null findings in TRANSCEND and PRoFESS likely reflect their low event rate and insufficient power to detect differences between telmisartan and placebo (14,15). In a prespecified pooled analysis of both trials, 12.8% of patients in the telmisartan group experienced a stroke, MI or cardiovascular death compared with 13.8% in the placebo group (RR, 0.91; 95%CI, 0.85 to 0.98); efficacy was particularly accentuated after the first six months of follow-up (RR, 0.85; 95%CI, 0.78 to 0.92). Collectively, this evidence base provides support for use of an ARB in patients with hypertension in association with CAD; however, as was the case before these trials, the accumulated weight of placebo-controlled trial evidence supports provision of ACE inhibitor therapy for this indication.

2. For hypertensive patients with CAD, but without coexisting systolic heart failure, the combination of an ACE inhibitor and ARB is not recommended (Grade B).

A Grade B recommendation was developed to avoid dual renin-angiotensin system (RAS) inhibition with combination ACE inhibitor and ARB therapy in patients with CAD, but without coexisting systolic heart failure. This recommendation is based on extrapolation of evidence of harm from the ONTARGET study (13,34). The ONTARGET study population was a high vascular risk group, in which 74% of patients had a history of stable CAD, and 49% a history of previous MI at baseline. Patients with heart failure were excluded from the study. Of note, several randomized trials (35,36) demonstrated a reduction in congestive heart failure hospitalizations or mortality with combination ACE inhibitor and ARB therapy.

3. For high-risk hypertensive patients, when combination therapy is being used, choices should be individualized. The combination of an ACE inhibitor and a dihydropyridine CCB is preferable to an ACE inhibitor and a thiazide/thiazide-like diuretic in selected patients (Grade A).

ACCOMPLISH (37,38) enrolled 11,506 patients aged 68.4 (±6.9 yrs.) years with hypertension who were at high risk for cardiovascular events by virtue of concomitant CAD (46%), stroke (13%), renal disease (6%), peripheral arterial disease (8%) or diabetes mellitus (60%). Patients were randomly assigned to receive a combination of benazepril and amlodipine, or a combination of benazepril and hydrochlorothiazide. The primary endpoint was the composite of death from cardiovascular causes, non-fatal MI, non-fatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest and coronary revascularization. Although control to less than 140/90 mm Hg was achieved in a remarkable 74% of trial participants, mean reduction in BP was slightly greater for the benazepril-amlodipine group than for the benazepril-hydrochlorothiazide group (difference of –0.9 mm Hg systolic and –1.1 mm Hg diastolic; P < 0.001 for both systolic and diastolic pressure differences).

The trial was terminated early after a mean follow-up period of 36 months. The primary outcome occurred in 9.6% of patients in the benazepril-amlodipine group compared with 11.8% of patients in the benazepril-hydrochlorothiazide group (HR, 0.80; 95%CI, 0.72 to 0.90). Although the majority of these events were coronary revascularization procedures, a benazepril-amlodipine combination was also superior in reducing risk of hard clinical endpoints including the traditional composite of death from cardiovascular causes, MI and stroke (RR, 0.79; 95%CI, 0.67 to 0.92).

The risk of serious drug-related adverse events was low and similar in both groups. Thus, results of ACCOMPLISH demonstrate benefits and tolerability of combination therapy in patients with poorly controlled BP.

4. For patients with stable angina pectoris but without previous heart failure, myocardial infarction, or coronary artery bypass surgery, either a β-blocker or CCB can be used as initial therapy (Grade B; revised recommendation).

The recommendation to use beta-adrenergic antagonists (β-blockers) in patients with stable angina and hypertension is based on extrapolation from the substantial body of literature in MI survivors showing convincing survival benefits with these drugs (thus, Grade B evidence) (19). The recommendation supporting use of long-acting CCBs in patients with stable angina is based on a meta-analysis of 90 trials comparing β-blockers with other agents in this patient population.  (20).

This recommendation is also supported by the PREVENT study, which showed statistically significant reductions in unstable angina and coronary revascularization in a placebo-controlled trial of amlodipine, but only warrants a Grade B recommendation because one must extrapolate from study population to patients with hypertension (21).

The International Verapamil-Trandolapril Study (INVEST) (25) supports the recommendation a long-acting CCB may be used in treating hypertensive patients with CAD. The INVEST study was a randomized controlled trial of 22,576 patients older than 50 years of age with CAD. The study compared a verapamil-based regimen with an atenolol-based regimen for the primary outcome of total mortality, MI and stroke for a mean follow-up of 2.7 years. In both treatment arms, more than two-thirds of patients were treated with two or more antihypertensives. No significant differences were demonstrated in the primary outcome between the two treatment groups with fairly narrow Cls, suggesting no clinically important differences existed. Also, there were no significant differences in any of the cardiovascular secondary outcomes between treatment groups.

The findings of INVEST are congruent with 2 other smaller trials, the Angina Prognosis Study in Stockholm (APSIS) and the Total Ischemic Burden European Trial (TIBET) (26,27). These 2 studies enrolled and randomized 809 and 682 patients, respectively, with stable angina to either a
b-blocker (ie, metoprolol in APSIS and atenolol in TIBET) or a CCB (verapamil in APSIS and nifedipine in TIBET). Both trials reported a comparable efficacy between b-blockers and CCBs in preventing major adverse cardiovascular events in patients with stable coronary disease. Notably, however, neither trial required hypertension to be present for study inclusion. Only a quarter of participants in APSIS had hypertension compared with approximately half of those in
TIBET. Nonetheless, the existing evidence as a whole supports the use of either a b-blocker or CCB as initial therapy in those with stable coronary disease.

5. Short-acting nifedipine should not be used (Grade D).

The recommendation to avoid short-acting nifedipine in patients with ischemic heart disease is derived from a meta-analysis of 60 trials comparing nifedipine with other active drugs in patients with angina, which showed a statistically significant increase in anginal episodes in short-acting nifedipine-treated patients (OR, 4.2; 95%CI, 1.4 to 12.5) (31). There were only 12 major events (MI, death, stroke) in these 60 trials, so conclusions about clinically important outcomes cannot be made; recognizing that anginal frequency is a non-validated surrogate outcome, this recommendation is a Grade D.

6. When decreasing SBP to target levels in patients with established CAD (especially if isolated systolic hypertension is present), be cautious when the DBP is ≤ 60 mm Hg because of concerns that myocardial ischemia might be exacerbated (Grade D).

Post hoc analyses of large clinical trials in patients with CAD suggest existence of a possible J-curve, in which BP lowering to less than a specific nadir – which varies between studies – is associated with an increased risk of coronary events (41–43). This J-curve is mirrored by evidence from some but not all cohort studies (60–62).

The only clinical trial to test this hypothesis in a prospective randomized fashion is the Hypertension Optimal Treatment (HOT) trial (63). In the HOT trial, 18,790 patients with diastolic hypertension were randomly allocated to three different DBP targets: 90 mm Hg, 85 mm Hg, or 80 mm Hg. During the trial, DBP was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg in these three target groups, respectively. Among the 3080 patients with CAD at baseline, the number of major cardiovascular events declined non-significantly in relation to target groups (77, 68, and 62 events in target groups 90 mm Hg, 85 mm Hg, and 80 mm Hg, respectively). A statistically significant reduction was demonstrated in risk of stroke (35, 30, and 20 events occurred in the three target groups; [P=0.046], with a relative risk reduction of 43% for 80 mm Hg target group compared with 90 mm Hg target group).

It is important to note that achieved DBP in patients with CAD randomized to the most intensive target averaged 81.1 mm Hg (standard deviation [SD], 5.0) after 6 months of follow-up, which implies the HOT Trial cannot fully evaluate risk-benefit trade-off for lowering DBP below this range.

The recommendation to exercise caution with lowering DBP to < 60 mm Hg is primarily derived from 3 studies – post hoc analyses of the Systolic Hypertension in Europe (Syst-Eur) trial (45), an observational coronary catheterization study (46), and a systematic review of benefits of BP reduction in patients with CAD (44). In the Syst-Eur trial, cardiovascular event rates were increased when on-treatment DBP levels were 70 mm Hg (independent of SBP levels) in older individuals (age ≥ 60 years) with CAD receiving active antihypertensive treatment. This increase in cardiovascular events appeared to reach statistical significance at a DBP value of ~ 60 mm Hg. An observational coronary catheterization study (46) demonstrated when central DBP was 60 mm Hg or less in hypertensive patients with CAD, probability of reduced coronary blood flow distal to coronary stenosis was increased. Finally, a recent systematic review (47) examining beneficial and harmful effects of BP-lowering drugs in patients with CAD indicated further reduction in cardiovascular disease event rates was small at SBP values < 140 mm Hg, and should be weighed against risk of hypotension.

Thus, there is Grade D evidence supporting the possibility of harm with excessive lowering of DBP in patients with established CAD. An alternative explanation might be that a lower DBP is a marker for frailty or medical illness and not causally related to increased events (48). Nevertheless, the RTF believed evidence was sufficiently robust to warrant bringing this issue to the attention of practitioners. The RTF wishes to emphasize that this evidence suggests caution when lowering BP but does not preclude BP-lowering, especially in patients with moderate or severely increased SBP levels. A cautious approach might involve observing more carefully for signs and symptoms of reduced coronary blood flow while lowering SBP. This recommendation does not apply to hypertensive patients without CAD.

Finally, even in the context of CAD, other diagnoses such as diabetes or chronic kidney disease (CKD) might support further increases in antihypertensive therapy to lower SBP even when DBP values are ≤ 60 mm Hg.

B. Recommendations for patients with hypertension who have had a recent myocardial infarction (MI)

1. Initial therapy should include a β-blocker and an ACE inhibitor (Grade A).

Most randomized clinical trials or treatments for ischemic heart disease (as well as for other cardiovascular diseases listed below) have studied drugs with antihypertensive properties, but they have not specifically addressed their effect in hypertensive patients with these particular disorders (49–53). Because there would be no biological rationale for effects of these drugs being qualitatively different in normotensive and hypertensive populations, evidence for the benefit of therapy on important outcomes, overall, has been extrapolated to the hypertensive subset of these study patients.

The recommendation to prescribe a β-blocker to patients with hypertension and a recent MI is based on a meta-analysis of 55 trials showing 20% to 25% reductions in mortality and re-infarction rates in β-blocker-treated patients post-myocardial infarction, including the subgroup with hypertension at baseline (19,54).

The recommendation to prescribe an ACE inhibitor to patients with hypertension and a recent MI is based on a meta-analysis of 98,496 patients showing statistically significant reductions in 30-day mortality in ACE inhibitor-treated patients post MI in the order of 5% to 10% (55). In many of the trials included in this meta-analysis, as well as in others such as the HOPE trial, benefits of ACE inhibitor therapy are similar irrespective of whether patients are taking β-blockers.

2. An ARB can be used if the patient is intolerant of an ACE inhibitor (Grade A in patients with left ventricular (LV) systolic dysfunction).

The RTF added a Grade A recommendation supporting use of ARBs in patients with recent MI and LV systolic dysfunction if patients are intolerant to ACE inhibitors, based on VALIANT study results. In the VALIANT study (56), 14,703 patients who had an acute MI complicated by heart failure or LV systolic dysfunction (ejection fraction of 35% or lower) were randomly assigned to valsartan alone, captopril alone or both valsartan and captopril. After a two-year median follow-up, there was no difference among the three groups for the primary endpoint of death from any cause (captopril versus valsartan; HR, 1.00; 95%CI, 0.90 to 1.11).

The CWG also reviewed TRANSCEND (14), the smaller sister study to ONTARGET (13). This trial studied 5926 patients with cardiovascular disease or high-risk diabetes, who were intolerant of ACE inhibitors. The patients were assigned randomly to receive telmisartan or placebo. Despite a greater BP reduction in the telmisartan group (–3.2/–1.3 mm Hg) over a mean of 2.5 years, there was no difference in the primary composite outcome of cardiovascular death, MI, stroke or hospitalization for heart failure (HR, 0.92; 95%CI, 0.81 to 1.05; P=0.2).

There was a modest difference in the pre-specified composite secondary outcome of cardiovascular death, MI and stroke in the telmisartan group (13.0%) compared with the placebo group (14.8%) (HR, 0.87; P=0.048). However, this difference became non-significant after statistical adjustments were made for multiple comparisons (P=0.068). These results from TRANSCEND do not alter CHEP recommendations for ischemic heart disease, and ACE inhibitors should continue to be used as first-line agents.

3. CCBs may be used in patients after MI when β-blockers are contraindicated or not effective. Nondihydropyridine (NDHP) CCBs should not be used when heart failure is present, evidenced by pulmonary congestion at time of examination or radiography (Grade D).

A meta-analysis of 28 trials with clinically important outcomes evaluating impact of CCBs post MI reveals summary odds ratios (OR) for death of 0.93 (95%CI, 0.78 to 1.10) with verapamil, 1.00 (95%CI, 0.80 to 1.24) with diltiazem, and 1.12 (95%CI, 0.96 to 1.30) with dihydropyridines (54–56). Because these agents are effective in reducing anginal episodes and blood pressure (non-validated surrogate outcomes in this population), the recommendation that these agents may be used warrants a Grade D. (29–31).

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