Effects of Blood Pressure Reduction in Mild Hypertension: A systematic Review and Meta-analysis

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Sundstrom J, et al. "Effects of blood pressure reduction in mild hypertension: a systematic review and meta-analysis". Annals of Internal Medicine. 2015. 162(3):184-191.
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Clinical Question

In patients with mild hypertension (grade 1 hypertension: SBP 140-159 and/or DBP 90-99) and no pre-existing cardiovascular disease, does treatment with antihypertensive agents, versus no treatment, help to prevent cardiovascular events and death?

Bottom Line

Antihypertensive therapy in patients in mild hypertension and no previous history of cardiovascular disease, does appear to reduce the risk of overall death (NNT=111), cardiovascular death (NNT=82) and stroke (NNT=172) but not cardiovascular events, coronary events and heart failure.

Major Points

  • It is well known that long term hypertension can lead to cardiovascular events and death in the general population. It is also known that epidemiological data suggests that there is a log-linear association between blood pressure and cardiovascular death. Most of the evidence available to support the use of antihypertensive agents however look at patients with grade 2 or 3 hypertension or patients with overall increased CVD risk. These findings are then extrapolated to suggest benefit in patients with grade 1 hypertension but the actual benefit is unknown and therefore questioned.
  • There was a systematic review by the Cochrane Collaboration done in 2012 which addressed this specific question, and suggested there is no benefit in these patients. That study however had many limited factors including exclusion of recent relevant trials, low study power and use of second-line treatment options for HTN such as beta-blockers.
  • This most recent systematic review and meta analysis now shows that treating mild hypertension is indeed likely to prevent stroke, overall death and cardiovascular death. All three of these are outcomes that patients are likely to care about and therefore are more likely to agree to treatment. Overall, it is still important to consider the patient's overall CVD risk as well as the size of blood pressure reduction that is achievable in each specific patient when making treatment decisions.

Guidelines

JNC 8 Hypertension Guidelines

  • In the general population <60 years, initiate pharmacologic treatment to lower BP at SBP ≥140 mm Hg and treat to a goal SBP <140 mm Hg. (Expert Opinion – Grade E)
  • In the general population <60 years, initiate pharmacologic treatment to lower BP at DBP ≥90 mm Hg and treat to a goal DBP <90 mm Hg. (For ages 30-59 years, Strong Recommendation – Grade A; For ages 18-29 years, Expert Opinion – Grade E)
  • In the general population aged ≥60 years, initiate pharmacologic treatment to lower blood pressure (BP) at systolic blood pressure (SBP) ≥150 mmHg or diastolic blood pressure (DBP) ≥90 mm Hg and treat to a goal SBP <150 mmHg and goal DBP <90 mm Hg. (Strong Recommendation – Grade A)

NICE Guidelines: Hypertension in Adults

  • Offer antihypertensive drug treatment to people aged under 80 years with stage 1 hypertension who have one or more of the following: target organ damage, established cardiovascular disease, renal disease, diabetes, A 10-year cardiovascular risk equivalent to 20% or greater
  • For people aged under 40 years with stage 1 hypertension and no evidence of target organ damage, cardiovascular disease, renal disease or diabetes, consider seeking specialist evaluation of secondary causes of hypertension and a more detailed assessment of potential target organ damage. This is because 10-year cardiovascular risk assessments can underestimate the lifetime risk of cardiovascular events in these people.

Design

  • This study was built on a systematic review recently published by the BPLTTC (Blood Pressure Lowering Treatment Trialists’ Collaboration) which looked to compare specific blood pressure lowering agents. The data obtained from these trials was then used in this study by pulling out specific subsets of participants who met the inclusion criteria specific in this review. In addition to the BPLTTC data, three additional trials were included in this analysis which were all published after May 2011.
  • Systematic review and meta analysis of 13 randomized controlled trials:
    • 10 BPLTTC trials
    • 3 non-BPLTCC trials
  • N=15266
    • BPLTTC trials (n=6363)
    • Non-BPLTCC trials (n=8905)
    • Treatment (n=7842)
    • Control (n=7424)
  • Setting: Multi-center
  • Mean Follow Up:
    • BPLTCC: 4.4 years
    • Non-BPLTCC: 4-5 years
  • Primary Outcome: Cardiovascular events and death

Population

Inclusion Criteria

  • Randomized, controlled trials
  • Duration > 1 year
  • Age >18
  • 80% patients with Grade 1 HTN
  • Compared either:
    • Antihypertensive medication as monotherapy vs. placebo
    • Stepped care algorithm vs placebo
    • Either of above compared to other control regimen

Exclusion Criteria

  • Patients with previous CVD (MI, angina, CABG, PCI, stroke, TIA, carotid surgery, PAD, intermittent claudication, renal failure)
  • No event contribution in any outcomes of interest

Baseline Characteristics

  • Avg patients per trial: 6361
  • Mean age: 63.5 (8.4)
  • Female: 40%
  • Mean total cholesterol (SD):
    • mmol/L: 5.4 (1.2)
    • mg/dL: 208.5 (46.3)
  • Smokers: 16%
  • Previous antihypertensive treatment:
    • BPLTTC trials: 61%
    • Non-BPLTTC trials: 0%
  • Diabetes mellitus:
    • BPLTTC trials: 96%
    • Non-BPLTTC trials: 0%
  • Mean BMI (SD): 29.2 (5.2)
  • Mean SBP (SD): 146 mmHg (7)
  • Mean DBP (SD): 84 mmHg (8)

Interventions

  • Antihypertensive therapy vs. Placebo
    • 10 trials compared using one anti-hypertensive therapy to placebo in patients with mild hypertension
    • Antihypertensive treatments used were ACE Inhibitors, non-DHP CCB, or a thiazide diuretic
  • More vs less intensive antihypertensive therapy
    • 3 trials compared using a less vs. more antihypertensive treatment regimen in patients with mild hypertension
    • There was no specification on which medications were used in these trials
  • Note: The authors included as a criticism that previous trials used beta-blockers as monotherapy, whereas the authors choose to exlcude those trials from this review.

Outcomes

Comparisons are anti-hypertensive (BPLTTC trials + non-BPLTTC trials) therapy vs. no therapy.

Primary Outcomes

  • Total major cardiovascular events: 3.97% vs. 4.71% (OR 0.86 CI 0.74-1.01)
    • Stroke (non-fatal stroke or death of cerebrovascular disease): 1.55% vs. 2.13% NNT=172 (OR 0.72 CI: 0.55-0.94)
    • Coronary events (non-fatal MI or fatal MI): 2.81% vs. 2.80% (OR 0.91 CI: 0.74-1.12)
    • Heart failure (death or hospitalization): 2.15% vs. 2.75% (OR: 0.80 CI: 0.57-1.12)
    • Cardiovascular Death: 3.15% vs. 4.27% NNT=82 (OR: 0.75 CI: 0.57-0.98)
  • Total death: 3.9% vs. 4.8% NNT=111 (OR: 0.78 CI: 0.67-0.92)
  • Overall withdrawal: 21% vs. 22.5% (Not all studies reported withdrawal rate. Significance not reported)
  • Withdrawal due to AE: 4.8% vs. 2.4% (Only reported in 1 study. Significance not reported)

Secondary Outcomes

  • Exclusion of subset of individuals who were >60 years, SBP <150 mmHg, no DM, following JNC 8 guidelines (excluded 75 people): The analysis did not differ from the above results.

Subgroup Analysis

  • 36 sets of subgroups were analyzed including: Study type, age, smoking, BMI, baseline SBP, baseline DBP, etc.)

Only nominally significant heterogeneity shown was cardiovascular death between men and women (p=0.02)

Adverse Events

  • The specific adverse events were not noted in this study and the withdrawal rate due to adverse events were only noted in 1 trial and this study did not list the specific adverse events. Also, it would be difficult to make conclusions of adverse events from 1 study because there are many different antihypertensive agents available with a wide array of adverse events.

Criticisms

  • Blood pressure reductions in almost all cases were modest (3.6/2.4 mmHg)
  • Event outcomes were low in both the active and control groups causing CI to be wide, thereby causing power to be limited.
  • Data on withdrawal rates and withdrawal rates due to adverse events were limited in that many studies did not report this information. Overall withdrawal rates were actually higher in the control groups which is not expected.
  • Although the patients did not have a documented history of CVD, many of the patients were likely enrolled in the trial due to having other risk factors such as diabetes (96% of the BPLTTC patients had diabetes). It is important to note however that on a subgroup analysis, the relative risk reduction in these patient populations did not change between these groups.
  • Patients with mild hypertension may already have subclinical cardiovascular damage which may have contributed to their cardiovascular risk.

Funding

  • Funding was provided by the National Health and Medical Research Council of Australia Program Grant and the BPLTCC received funding from Astra Ha ̈ ssle, Bayer, British Heart Foundation, Bristol-Myers Squibb, Glaxo Wellcome, Hoechst Marion Roussel, Knoll, Merck & Co., Pfizer, Searle, and Institut de Recherches Internationales Servier.
  • The funding source had no role in the design, collection, analysis, interpretation or decision to approve publication of the study

Further Reading

  1. Sundström J, Arima H, Jackson R, Turnbull F, Rahimi K, Chalmers J et al. Effects of Blood Pressure Reduction in Mild Hypertension. Annals of Internal Medicine. 2015;162(3):184.
  2. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD006742. DOI: 10.1002/14651858.CD006742.pub2
  3. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520. doi:10.1001/jama.2013.284427.
  4. Hypertension. Clinical management of primary hypertension in adults. London (UK): National Institute for Health and Clinical Excellence (NICE); 2011 Aug.