IV. Global Vascular Protection Therapy for Adults with Hypertension without Compelling Indications for Specific Agents

Prevention and Treatment

Subgroup Members: Ross D. Feldman, MD; Ernesto L. Schiffrin, MD, PhD; Robert A. Hegele, MD; Philip A. McFarlane, MD, PhD; Andrew Pipe, C.M., MD; Paul Oh, MD; Peter Selby, MBBS, MHSc; Milan Khara, MBChB; Milan Gupta, MD
Central Review Committee: Stella S. Daskalopoulou, MD, PhD; Kaberi Dasgupta, MD, MSc; Kelly B. Zarnke, MD, MSc; Kara Nerenberg, MD, MSc; Alexander A. Leung, MD, MPH; Kevin C. Harris, MD, MHSc; Kerry McBrien, MD, MPH; Sonia Butalia, BSc, MD; Meranda Nakhla, MD, MSc
Chair: Doreen M. Rabi, MD, MScThis information is based on the Hypertension Canada guidelines published in Leung, Alexander A. et al. Hypertension Canada’s 2017 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults. Can J Cardiol 2017; 33(5): 557-576.

Guidelines

  1. Statin therapy is recommended in hypertensive patients with 3 or more cardiovascular risk factors as defined in Supplemental Table S11 (Grade A in patients >40 years) or with established atherosclerotic disease (Grade A regardless of age).
  2. Consideration should be given to the addition of low-dose acetylsalicylic acid (ASA) therapy in hypertensive patients ≥50 years of age (Grade B). Caution should be exercised if BP is not controlled (Grade C).
  3. Tobacco use status of all patients should be updated on a regular basis and health care providers should clearly advise patients to quit smoking (Grade C).
  4. Advice in combination with pharmacotherapy (e.g., varenicline, bupropion, nicotine replacement therapy) should be offered to all smokers with a goal of smoking cessation (Grade C).
  5. For high-risk patients (Table 3), aged ≥50 years, with systolic BP levels ≥130 mmHg, intensive management to target a systolic BP ≤120 mmHg should be considered. Intensive management should be guided by automated office BP measurements (see Diagnosis and Assessment Guidelines, Section I [Accurate measurement of BP], and Supplemental Table S2 [Recommended Technique for Automated Office BP]). Patient selection for intensive management is recommended and caution should be taken in certain high-risk groups (Table 4; Grade B).

Background

1. Statin therapy is recommended in hypertensive patients with 3 or more cardiovascular risk factors as defined in Supplemental Table S11 (Grade A in patients >40 years) or with established atherosclerotic disease (Grade A regardless of age).

Although BP-lowering medications form the nidus of the therapeutic recommendations in these guidelines, we also wish to emphasize that other anti-atherosclerotic medications may confer further cardiovascular benefit in selected individuals with hypertension. As outlined in the Diagnostic recommendations, all hypertensive patients should be screened for dyslipidemia and diabetes mellitus. In hypertensive patients found to have hyperlipidemia or hyperglycemia, the CHEP recommendations endorse the Working Group on Hypercholesterolemia and Other Dyslipidemias guidelines (1) and the Canadian Diabetes Association (2) with respect to treatment thresholds, targets and choice of agents.

However, on the basis of four randomized trials, which included large numbers of hypertensive patients with lipid levels that traditionally would not be deemed elevated, a recommendation that statin therapy be given to selected hypertensive patients considered to be at high risk of cardiovascular risk (i.e., having at least three of the risk factors listed in Table 1) was added. This recommendation is identical to that proposed for statin therapy to those defined as fulfilling the same criteria and described as “high risk hypertension” in the 2012 Update of the Dyslipidemia Guidelines.

In the ASCOT-LLA trial (3), 10,305 individuals with hypertension (aged 40 to 79 years, mean age 63 years), at least three other cardiovascular risk factors (see Table 1) and a total cholesterol level of 6.5 mmol/L or lower, were randomly assigned to atorvastatin 10 mg or to placebo (mean BP at baseline was 164/95 mm Hg). Patients with known coronary disease or recent stroke as well as those needing lipid-lowering therapy by their primary care physicians were excluded. The mean low-density lipoprotein (LDL) cholesterol at baseline was 3.4 mmol/L, and over a median follow-up of 3.3 years, the atorvastatin-treated patients had a mean reduction in LDL of 1.1 mmol/L versus placebo. There was a significant reduction in the incidence of fatal and nonfatal myocardial infarction (MI) with atorvastatin (HR 0.64; 95%CI, 0.50 to 0.83, number needed-to-treat [NNT]=294 patient-years). Further, relative benefits were consistent irrespective of baseline total cholesterol concentrations. Stroke (HR 0.73; 95%CI, 0.56 to 0.96) and total cardiovascular events (HR 0.79; 95%CI, 0.69 to 0.90) were also significantly reduced with atorvastatin, and there was a strong trend toward reduced all-cause mortality (HR 0.87; 95%CI, 0.7 to 1.06).

In ALLHAT-LLT trial (4), 10,355 hypertensive patients (mean pressure of 145/84 mm Hg), older than age 55 years (mean age 66 years), with at least one additional cardiovascular risk factor were randomly assigned to either pravastatin 40 mg daily or to placebo. Mean LDL cholesterol was 3.8 mmol/L at baseline, and over five years of follow-up, mean reduction in the pravastatin arm was only 0.6 mmol/L greater than in the placebo arm (the fact that almost one-third of placebo patients started a lipid-lowering drug during the trial, and that 23% of pravastatin patients discontinuing therapy before the end of the trial, most likely attributed to lack of significant reduction).

Perhaps as a result of the small difference in LDL cholesterol lowering between treatment arms, primary outcome (all-cause mortality) was not significantly different with pravastatin therapy (RR 0.99; 95%Cl; 0.89 to 1.11). Although there were trends toward less fatal and nonfatal MI (RR 0.91; 95%Cl, 0.79 to 1.04) and less fatal and nonfatal stroke (RR 0.91; 95%CI, 0.75 to 1.09) with pravastatin, these differences did not reach statistical significance.

The PROSPER trial (5) was conducted in 5804 patients aged 70 years to 82 years (mean 75 years) with a history of vascular disease or risk factors (hypertension, smoking or diabetes mellitus) and total cholesterol concentration of 4.0 mmol/L to 9.0 mmol/L. Patients were randomly assigned to pravastatin 40 mg daily or to placebo, and after 3.2 years of follow-up, the mean reduction in LDL was 1.0 mmol/L in the pravastatin group versus placebo (from a baseline of 3.8 mmol/L). The primary endpoint of nonfatal Ml, fatal/nonfatal stroke and coronary death was significantly reduced (HR 0.85; 95%CI, 0.74 to 0.97, NNT=l52 patient-years), with similar benefits in the 62% of trial participants with hypertension as in those without hypertension. Similar to ASCOT-LLA, there were no differences in efficacy across baseline cholesterol levels (interaction, P=0.69).

In the Medical Research Council/British Heart Foundation (MRC/BHF) Heart Protection Study (6), 20,536 patients (aged 40 years to 80 years) were randomly assigned to simvastatin 40 mg daily or to placebo if they had non-fasting total cholesterol of 3.5 mmol/L or greater, and were thought to be at an increased risk because of presence of atherosclerotic vascular disease, diabetes mellitus or hypertension in men over 65 years of age. Interestingly, patients were excluded if their primary care physician thought they should be on statin therapy. Mean LDL cholesterol was 3.4 mmol/L at baseline and was lowered by 1.0 mmol/L in the simvastatin arm versus the placebo arm. The primary outcome (all-cause mortality) was reduced significantly with simvastatin therapy (HR 0.87; 95%CI, 0.81 to 0.94, NNT=278 patient-years), as was the composite outcome of the first major vascular event (HR 0.76; 95%CI, 0.72 to 0.81). The benefits of simvastatin were similar in the 41% of trial participants with hypertension as in those patients without hypertension (HR 0.80 versus 0.78), and no difference was seen in efficacy across baseline LDL cholesterol levels.

Of note, in the Heart Protection Study, benefits were seen with statin therapy over and above benefits of other cardioprotective treatments such as ASA, angiotensin-converting enzyme (ACE) inhibitors and beta-blockers (β-blockers) (these subgroups were not predefined or reported in ASCOT-LLA or PROSPER).

Although benefits of statins in such patients appear to be independent of baseline cholesterol levels, trials to date have only included patients with normal or high-normal cholesterol concentrations; therefore, further research is needed to determine whether there is a cholesterol level below which statin therapy would not be beneficial.

2. Consideration should be given to the addition of low-dose acetylsalicylic acid (ASA) therapy in hypertensive patients ≥50 years of age (Grade B). Caution should be exercised if BP is not controlled (Grade C).

The recommendation to consider ASA for primary prevention of cardiovascular disease in hypertensive patients is based primarily on the Hypertension Optimal Trial (HOT) (7). In this trial, 18,790 patients aged 50 to 80 years (mean age, 61.5 +/- 7.5 years) with diastolic blood pressure (DBP) levels between 100 and 115 mm Hg were randomized using a 3 2 factorial design to 1 of 3 DBP targets (90 vs. 85 vs. 80 mm Hg) and to ASA vs. placebo. Over a mean follow-up time of 3.8 years, ASA therapy reduced incidence of major cardiovascular events (MACE) from 10.5% to 8.9% (HR 0.85; 95%CI, 0.73–0.99). When silent myocardial infarctions (MI) were included in the MACE end point, overall results were inconclusive (HR, 0.91; 95%CI, 0.79–1.04) (7). It is unclear if MIs were an a priori component of the primary end point. On re-review of the trial and protocol (8), the recommendation to give low-dose ASA in hypertensive patients was downgraded to Grade B because of this uncertainty.

A second alteration was made in 2015 to the recommendation: Previously, the Recommendations Task Force (RTF) recommended that ASA treatment be considered in all hypertensive individuals, with a Grade A rating for those ≥ 50 years of age (9). This recommendation was modified recently such that it is restricted to hypertensive patients ≥ 50 years of age, and is more consistent with the population included in the HOT trial. This change also took into consideration benefits of ASA therapy in terms of reductions in MACE, and in prevention of cancer and ASA-associated bleeding risks (10,11). The RTF did not conduct in-depth modeling of these factors, which are beyond the scope of CHEP’s mandate, but did note that an age threshold of 50 years was consistent with recommendations of other organizations that have performed such analyses (10,12).

3. Tobacco use status of all patients should be updated on a regular basis and health care providers should clearly advise patients to quit smoking (Grade C).

Cigarette smoking is a well-established, independent, and powerful risk factor for vascular disease (14). Smoking cessation is thus a critically important component of global vascular risk reduction in hypertensive patients. The RTF reviewed data that demonstrated advice on smoking cessation and pharmacotherapy for smoking cessation are both effective strategies in assisting patients to quit smoking.

In a 2013 Cochrane collaboration systematic review that examined 42 randomized controlled trials of ≥ 6 months duration, brief physician advice to stop smoking led to clinically important increases in smoking cessation (15). Participants who received brief advice (provided in one 20-minute consultation with only 1 follow-up visit) were 66% (95%CI, 42%–94%) more likely no longer to be smoking at 6 months. Sustained smoking cessation occurred in 455 of 7913 (5.8%) patients who received minimal advice vs. 216 of 5811 (3.7%) patients who received usual care. More complex interventions (verbal advice combined with printed materials; additional support from another health care worker; or referral to a cessation clinic) were only slightly more effective.

4. Advice in combination with pharmacotherapy (e.g., varenicline, bupropion, nicotine replacement therapy) should be offered to all smokers with a goal of smoking cessation (Grade C).

A Cochrane Collaboration network meta-analysis (16) synthesized results from 12 reviews, which included efficacy data from 267 randomized controlled trials, and reported combining advice to quit smoking with pharmacotherapy significantly increased smoking cessation rates over follow-up periods of ≥ 6 months. Cessation advice combined with nicotine replacement therapy resulted in an 84% higher likelihood of sustained quitting compared with advice combined with placebo (data from 119 randomized controlled trials; OR, 1.84; 95%CI, 1.71–1.99). Similarly, advice combined with the antidepressant bupropion resulted in an 82% greater likelihood of sustained quitting (data from 36 randomized controlled trials; OR, 1.82; 95%CI, 1.60–2.06). Finally, advice combined with varenicline led to a nearly three-fold greater likelihood of quitting compared with advice combined with placebo (data from 15 randomized controlled trials; OR, 2.88; 95%CI, 2.40–3.47).

Table 3. Clinical indications defining high-risk patients as candidates for intensive management
* Four-variable Modification of Diet in Renal Disease (MDRD) equation.
Framingham Risk Score.
Clinical or sub-clinical cardiovascular disease
or
Chronic kidney disease (non-diabetic nephropathy, proteinuria <1 g/d, *estimated glomerular filtration rate 20-59 mL/min/1.73 m2)*
or
Estimated 10-year global cardiovascular risk 15%
or
Age ≥ 75 years
Patients with 1 or more clinical indications should consent to intensive management

5. For high-risk patients (Table 3), aged ≥50 years, with systolic BP levels ≥130 mmHg, intensive management to target a systolic BP ≤120 mmHg should be considered. Intensive management should be guided by automated office BP measurements (see Diagnosis and Assessment Guidelines, Section I [Accurate measurement of BP], and Supplemental Table S2 [Recommended Technique for Automated Office BP]). Patient selection for intensive management is recommended and caution should be taken in certain high-risk groups (Table 4; Grade B).

In 2016, a new recommendation to consider intensive BP control targeting an SBP ≤ 120 mm Hg in selected high-risk patients.

This recommendation is based primarily upon the Systolic Blood Pressure Intervention Trial (SPRINT) (17).

SPRINT was a randomized controlled trial that enrolled 9631 individuals at high risk for cardiovascular disease (but without diabetes, heart failure or previous stroke) and randomized them to receive either intensive treatment (targeting an SBP < 120 mm Hg) or standard control (targeting an SBP < 140 mm Hg). The trial was terminated after only 3.26 years because of a significant reduction in adverse cardiovascular events with intensive BP control that was detected before the end of the planned 5 years of follow-up. For the primary outcome of interest (a composite of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes), individuals who received intensive treatment had an event rate of 1.65% per year compared with 2.19% per year in those assigned to standard treatment (HR, 0.75; 95% CI, 0.64-0.89). Among individuals with normal kidney function at baseline, intensive control was associated with an increased risk of renal deterioration compared with standard treatment (HR, 3.49; 95% CI, 2.44-5.10). Serious adverse events commonly occurred but were similar in both groups (38.3% vs. 37.1% for intensive vs. standard treatment; P 1⁄4 0.25). Although our new treatment recommendation is largely on the basis of the findings of SPRINT, it is also consistent with those of 2 recent meta-analyses of randomized controlled trials, likewise reporting a strong linear association between lower SBP targets and a reduction in major adverse cardiovascular events (18,19).

In selected high-risk patients who might potentially benefit from lower BP targets, several major considerations should be made before implementing an intensive treatment strategy. First, risk evaluation should be primarily informed by the inclusion criteria used in the SPRINT trial (Table 5). Second, the risks and benefits of intervention should be carefully weighed, because patients with hypertension are at risk for adverse vascular events and also for adverse treatment effects. Caution should be exercised in the setting of clinical conditions in which evidence supporting lower SBP targets < 120 mm Hg remains limited, and therefore intensive BP lowering is more difficult to justify in light of the increased risk of adverse treatment effects (Table 6). Third, treatment should be guided by AOBP measurements (see The 2016 CHEP Diagnosis and Assessment Recommendations, Section I [Accurate Measurement of BP] as was the case in the SPRINT trial. Finally, patients should be prepared for more clinical encounters, monitoring, and medication usage. Individuals who received intensive treatment in SPRINT were followed monthly until target BP levels were achieved. On average, they were prescribed 2.7 antihypertensive agents, compared with 1.8 agents in the standard control group.

Table 4. Generalizability of intensive blood pressure-lowering: cautions and contraindications
eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure.
Limited or no evidence

  • Heart failure (ejection fraction < 35%) or recent myocardial infarction (within past 3 months)
  • Indication for, but not currently receiving, a beta-blocker
  • Institutionalized elderly

Inconclusive evidence

  • Diabetes mellitus
  • Previous stroke
  • eGFR <20 mL/min/1.73 m2

Contraindications

  • Patient unwilling or unable to adhere to multiple medications
  • Standing SBP <110 mm Hg
  • Inability to measure SBP accurately
  • Known secondary cause(s) of hypertension

References

  1. Genest J, Frohlich J, Fodor G, McPherson R. Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: Summary of the 2003 update. CMAJ 2003;169:921-4.
  2. Meltzer S, Leiter L, Daneman D, et al. 1998 clinical practice guidelines for the management of diabetes in Canada. Canadian Diabetes Association. CMAJ 1998;159(Suppl8):S1-29.
  3. Sever PS, Dahlof B, Poulter NR, et al., for the ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than- average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): A multicentre, randomised controlled trial. Lancet 2003;361:1149-58.
  4. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs. usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998-3007.
  5. Shepherd J, Blauw OJ, Murphy MB, et al., for the PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk: Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial. Lancet 2002;360:1623-30.
  6. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised, placebo-controlled trial. Lancet 2002;360:7-22.
  7. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351:1755-62.
  8. Hansson L, Zanchetti A; for the HOT Study Group. The hypertension optimal treatment study (the HOT study). Blood Press 1993;2:62-8.
  9. Hackam DG, Quinn RR, Ravani P, et al. The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, and assessment of risk, prevention, and treatment of hypertension. Can J Cardiol 2013;29:528-42.
  10. Calonge N, Petitti DB, DeWitt TG, Gordis L. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009;150:396-404.
  11. Rothwell PM, Fowkes FG, Belch JF, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011;377:31-41.
  12. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines [erratum in 2012;141:1129]. Chest 2012;141(suppl. 2):e637S-68S.
  13. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989;321:129-35.
  14. Teo KK, Ounpuu S, Hawken S, et al. Tobacco use and risk of myocardial infarction in 52 countries in the INTERHEART study: a case-control study. Lancet 2006;368:647-58.
  15. Stead LF, Hartmann-Boyce J, Perera R, Lancaster T. Telephone counselling for smoking cessation. Cochrane Database Syst Rev 2013:CD002850.
  16. Cahill K, Lancaster T. Workplace interventions for smoking cessation. Cochrane Database Syst Rev 2014:CD003440.
  17. Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-16.
  18. Ettehad D, Emdin CA, Kiran A, et al. Blood pressure lowering for 175 prevention of cardiovascular disease and death: a systematic review and 175 meta-analysis. Lancet 387;957-67.
  19. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering 175 on cardiovascular and renal outcomes: updated systematic review and 176 meta-analysis. Lancet 2016;387:435-43.