II. Indications for Drug 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. Antihypertensive therapy should be prescribed for average DBP measurements of ≥ 100 mm Hg (Grade A) or average SBP measurements of ≥ 160 mm Hg (Grade A) in patients without macrovascular target organ damage or other cardiovascular risk factors.
  2. Antihypertensive therapy should be strongly considered if DBP readings average ≥ 90 mm Hg in the presence of macrovascular target organ damage or other independent cardiovascular risk factors (Grade A).
  3. Antihypertensive therapy should be strongly considered if SBP readings average ≥ 140 mm Hg in the presence of macrovascular target organ damage (Grade C for 140–160 mm Hg; Grade A for > 160 mm Hg).
  4. Antihypertensive therapy should be considered in all patients meeting indications 1–3 in this section, regardless of age (Grade B). Caution should be exercised in elderly patients who are frail.
  5. In the very elderly (age ≥ 80 years) patients who do not have diabetes or target organ damage, the SBP threshold for initiating drug therapy is ≥ 160 mm Hg (Grade C).

Background

1. Antihypertensive therapy should be prescribed for average DBP measurements of ≥ 100 mm Hg (Grade A) or average SBP measurements of ≥ 160 mm Hg (Grade A) in patients without macrovascular target organ damage or other cardiovascular risk factors.

Population-based epidemiological studies establish clearly that risk of cardiovascular events, including stroke, myocardial infarction and heart failure, increases in a log-linear fashion with increased BP (1–4). (Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-1913.) Further, numerous trials show antihypertensive therapy reduces relative risk of cardiovascular events by approximately 25% to 30%, irrespective of pre-treatment BP, (at least for diastolic BPs in excess of 90 mm Hg) — of course, Early trials generally enrolled patients with diastolic blood pressures in excess of 90 mm Hg and later trials enrolled patients with elevated systolic blood pressure (often greater than 160 mmHg) (5-8).

Recommendations for hypertension management emphasize the importance of cardiovascular risk assessment when making treatment decisions. It is well known the risk of cardiovascular disease in hypertensive patients with identical blood pressure (BP) readings can vary more than 10-fold, depending on presence of other cardiovascular risk factors, hypertension-related complications, cardiovascular diseases or other illnesses (3,12,13). Patients with Stage II hypertension (≥160/100 mmHg), those with known cardiovascular disease, and those with multiple risk factors are at highest risk.

2. Antihypertensive therapy should be strongly considered if DBP readings average ≥ 90 mm Hg in the presence of macrovascular target organ damage or other independent cardiovascular risk factors (Grade A).

The meta-analytic data cited above supports this recommendation. Many of the early trials in the field of hypertension were based upon the randomization of subjects with elevated diastolic blood pressure. The Hypertension Detection and Follow-up Program (HDFP), a 5-year pragmatic randomized trial comparing an intensive antihypertensive treatment program with usual care, is a notable example. This trial reported a statistically significant 17% reduction in total mortality in the overall trial (14). Mortality was also reduced (5.9% with active treatment vs. 7.4% for usual care; P < 0.01) in the subgroup of 7825 patients with DBP levels between 90 and 104 mm Hg (10). Relative risk reductions were similar across BP strata (90–94, 95–99, and 100–104 mm Hg respectively).

3. Antihypertensive therapy should be strongly considered if SBP readings average ≥ 140 mm Hg in the presence of macrovascular target organ damage (Grade C for 140–160 mm Hg; Grade A for > 160 mm Hg).

The Grade C recommendation is to initiate pharmacotherapy for those patients with systolic BPs of 140 mm Hg to 159 mm Hg with concurrent macrovascular target organ damage. This recommendation to lower treatment threshold for high-risk patients derives from observational data and extrapolation from the Heart Outcomes Prevention Evaluation (HOPE) study (23) and from the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) (24). A meta-analysis of 61 prospective observational studies (12.7 million person-years) demonstrated for every 20 mm Hg increment in usual systolic BP (SBP), an associated two-fold difference occurs in stroke and cardiovascular death rate (25). Large cohort studies demonstrate consistently SBP has a strong, continuous, and graded association with cardiovascular morbidity and mortality, and there is no clear threshold value that distinguishes those patients at increased risk (25).

In the HOPE study (23), 9297 patients (≥ 55 years of age) with evidence of macrovascular target organ damage or diabetes, plus one other cardiovascular risk factor, who had a mean BP at entry of 139/79 mm Hg, were randomly assigned to ramipril or to placebo therapy. Study results showed a significant risk reduction in incidence of myocardial infarction (MI), stroke and cardiovascular death with ramipril use compared with placebo (RR 0.78; 95%CI 0.70 to 0.86; P<0.001). Those with SBPs above and below 138 mm Hg had similar benefits with use of ramipril (26). PROGRESS randomly assigned 6105 patients with a history of stroke or transient ischemic attack to perindopril, with or without indapamide or placebo. With a mean BP at study entry of 157/89 mm Hg, active treatment lowered BP by 9/4 mm Hg and conferred a reduction in total vascular events of 26% (24).

No recommendation has been made for the treatment of Stage 1 hypertension (BP 140–159/90–99 mm Hg) and no cardiovascular disease and, therefore, this is a gap within the CHEP treatment guidelines. Meta-analytic data do support the premise that the treatment of patients with Stage 1 hypertension (BP 140–159/90–99 mm Hg) and no cardiovascular disease is beneficial; however, the accumulated data are not as compelling as those supporting drug treatment of higher levels of BP or higher risk individuals and NNTs are higher (25).

With respect to the treatment of Stage 1 hypertension, two points deserve emphasis: First, non-pharmacological management should be instituted in all patients and, if successful, can potentially normalize BP levels without need for drug therapy. Second, the decision to initiate pharmacological treatment and timing of initiation should be guided by individual global cardiovascular risk assessment. In low-risk patients, including those without other cardiovascular risk factors or target organ damage, an extended interval of non-pharmacological management alone, with appropriate monitoring of BP levels, can be used. However, if non-pharmacological management is unsuccessful or if patients progress to Stage II hypertension, antihypertensive drug therapy should be considered.

4. Antihypertensive therapy should be considered in all patients meeting indications 1–3 in this section, regardless of age (Grade B). Caution should be exercised in elderly patients who are frail.

Randomized trials of antihypertensive therapy demonstrate clear benefit across many subgroups of hypertensive patients (28). However, elderly patients were sometimes excluded from these trials. Because chronological age does not necessarily reflect biological age, it is unlikely that the benefits of antihypertensive drug therapy summarized above for indications 1-3 cease to exist at a given age threshold. This underpins the rationale for this recommendation; the downgrade to a B reflects extrapolation from trials in the non-elderly.

5. In the very elderly (age ≥ 80 years) patients who do not have diabetes or target organ damage, the SBP threshold for initiating drug therapy is ≥ 160 mm Hg (Grade C).

(Note: in high-risk very elderly meeting the criteria of the SPRINT Trial, intensive blood pressure reduction can be considered, as outlined in the Global Vascular Protection section).

In 2013, CHEP introduced a < 150 mm Hg SBP treatment target for adults 80 years of age or older (see Recommendation 2 in Section V. Goals of Therapy for Adults With Hypertension Without Compelling Indications for Specific Agents). Then in 2014, the RTF added a ≥ 160 mm Hg pharmacotherapy treatment initiation threshold.

This recommendation is based on data from the Hypertension in the Very Elderly Trial (HYVET) (33,34) and from a meta-analysis from Gueyffier and colleagues (35). The HYVET enrolled 3845 hypertensive adults (defined as SBP of ≥ 160 mm Hg) aged 80 years or older, and randomized to active vs. placebo treatment in which the active treatment arm received indapamide 1.5 mg with or without perindopril (2–4 mg) to achieve a target BP of < 150/80 mm Hg. The primary outcome of the trial was stroke (fatal and non-fatal), with all-cause mortality as a predefined secondary outcome. The trial was stopped early (median follow-up was 1.8 years) when a planned interim analysis demonstrated active treatment to be associated with a lower risk of stroke (hazard ratio [HR], 0.59; 95%CI, 0.40–0.88) and all-cause mortality (HR, 0.76; 95%CI, 0.62–0.93).

However, the final time-to-event analysis, which was completed after the trial was stopped and all endpoints were counted (33), revealed the active treatment effect was no longer conclusive with respect to stroke (HR, 0.70; 95%CI, 0.49–1.01), but that there was still a conclusive 21% reduction in the risk of all-cause mortality (HR, 0.79; 95%CI, 0.65–0.95).

The RTF continues to recommend an SBP treatment target of < 150 mm Hg; however, in line with HYVET procedures, SBP threshold for initiation of treatment is now specified as 160 mm Hg. As noted in the 2013 CHEP Recommendations, the HYVET population had low rates of comorbid disease and adverse events during treatment. Subjects with orthostatic hypotension were likely excluded because standing SBP had to be ≥ 140 mm Hg at the last visit before randomization. Therefore the RTF continues to recommend caution when applying this Recommendation to frail elderly patients. For patients with SBP of 150–160 mm Hg, providers should exercise clinical judgement when deciding whether to initiate drug treatment, and should note that non-pharmacological therapy is still indicated for all patients.

Further support for the ≥ 160 mm Hg SBP pharmacologic treatment threshold in the very elderly population comes from the pre-HYVET meta-analysis by Gueyffier and colleagues (35), evaluating efficacy of hypertension treatment in patients ≥ 80 years of age. These investigators included data from seven trials, which compared efficacy of active treatment with either placebo, with no treatment, or with decreased doses of active treatment on the primary outcome of fatal and non-fatal stroke. Five of the seven trials enrolled patients with SBP levels ≥ 160 mm Hg. Among participants randomized to active treatment (n= 874), there were 57 strokes and 34 stroke deaths, compared with 77 strokes and 28 stroke deaths among participants randomized to the comparator groups (n= 796). The risk for stroke was 34% less (relative risk, 0.66; 95%CI, 0.48–0.92) among those in the active treatment arms. Taken together, this meta-analysis (35) and HYVET (34,34) provide evidence that treatment initiated at a threshold of ≥ 160 mm Hg reduces cardiovascular events and all-cause mortality in elderly patients.

References

  1. Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA 1996;275:1571-6.
  2. Padwal R, Straus SE, McAlister FA. Cardiovascular risk factors and their impact on the decision to treat hypertension: an evidence-based review. BMJ 2001;322:977-80.
  3. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765-74.
  4. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-1913.
  5. Gueyffier F. Boutitie F. Boisset JP, et al. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men. A meta-analysis of individual patient data from randomized, controlled trials. The INDANA Investigators. Ann Intern Med 1997;126:761-7.
  6. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827-38.
  7. Blood Pressure Lowering Treatment Trialists Collaboration. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014;384:591-598.
  8. Neal B, MacMahon S, Chapman N, for the Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet 2000;356:1955-1964.
  9. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database Syst Rev 2012:CD006742.
  10. Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension Detection and Follow-up Program Cooperative Group. JAMA 1979;242:2562-71.
  11. Ramsay LE, Wallis Ej, Yeo WW, Jackson PR. The rationale for differing national recommendations for the treatment of hypertension. Am J Hypertens 1998;11:79S-88S.
  12. Dahlof B, Lindholm LH, Hansson L, Schersten B, Ebkom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991;338:1281-85.
  13. Anderson KM, Wilson PWF, Odell PW, Kannel WB. An updated coronary risk profile. A statement for health professionals. Circulation 1991;83:356-62.
  14. Hypertension Detection and Follow-up Program. Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension Detection and Follow-up Program Cooperative Group. JAMA 1979;242:2562-2571.
  15. Alderman MH. Measures and meaning of blood pressure. Lancet 2000;355:159.
  16. McAlister FA, Laupacis A. Towards a better yardstick: the choice of treatment thresholds in hypertension. Can J Cardiol 1998;14:47-51.
  17. McAlister FA, Levine M, Zarnke K, Campbell NRC, et al., for the Canadian Hypertension Recommendations Working Group. The 2000 Canadian Recommendations for the management of hypertension: Part one – Therapy. Can J Cardiol 2001;17:543-59.
  18. Jackson R, Barham P, Bills J, Birch T, McLennan L. Management of raised blood pressure in New Zealand. A discussion document. BMJ 1993;307:107-10.
  19. McAlister FA, Laupacis A. Towards a better yardstick: the choice of treatment thresholds in hypertension. Can J Cardiol 1998;14:47-51.
  20. Deber RB, Kraetschmer N, Irvine J. What role do patients wish to play in treatment decision-making? Arch Intern Med 1996;156:1414-20.
  21. McAlister FA, O’Connor AM, Wells G, Grover SA, Laupacis A. When should hypertension be treated? The different perspectives of Canadian family physicians and patients. CMAJ 2000;163:403-8.
  22. Steel N. Thresholds for taking antihypertensive drugs in different professional and lay groups: questionnaire survey. BMJ 2000;320:1446-7.
  23. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin- converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:I45-53.
  24. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure- lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:I033-4l. (Errata in 2001;358:1556 and 2002;359:2120).
  25. Sundström J, Arima H, Jackson R, Turnbull F, Rahimi K, Chalmers J, Woodward M, Neal B. Effects of Blood Pressure Reduction in Mild Hypertension. Ann Intern Med 2015;162:184.
  26. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345: 1291-7.
  27. Sleight P, Yusuf S, Pogue J, Tsuyuki R, Oiaz R, Probstfield J; Heart Outcomes Prevention Evaluation (HOPE) Study. Blood-pressure reduction and cardiovascular risk in HOPE study. Lancet 2001;358:2130- l.
  28. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: Results of prospectively designed overviews of randomised trials. Lancet 2000;356:1955-64.
  29. Gueyffier F, Bulpitt C, Boissel JP, et al. Antihypertensive drugs in very old people: A subgroup meta-analysis of randomized controlled trials. Lancet 1999;353:793-6.
  30. Oates DJ, Berlowitz DR, Glickman ME, Silliman RA, Borzecki AM. Blood pressure and survival in the oldest old. J Am Geriatr Soc 2007;55:383-8.
  31. Beckett NS, Peters R, Fletcher AE, et al; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887-98.
  32. Chow CM, Donovan L, Manuel D, Johansen H, Tu JV; Canadian Cardiovascular Outcomes Research Team. Regional variation in self-reported heart disease prevalence in Canada. Can J Cardiol 2005;21:1265-71.
  33. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887-98.
  34. Beckett N, Peters R, Tuomilehto J, et al. Immediate and late benefits of treating very elderly people with hypertension: results from active treat- ment extension to Hypertension in the Very Elderly randomised controlled trial. BMJ 2012;344:d7541.
  35. Gueyffier F, Bulpitt C, Boissel JP, et al. Antihypertensive drugs in very old people: a subgroup meta-analysis of randomised controlled trials. INDANA Group. Lancet 1999;353:793-6.