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Editor's Note: Commentary based on Blood Pressure Lowering Treatment Trialists' Collaboration, Sundström J, Arima H, et al. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014;384:591-8.

Background

Guidelines for the management of blood cholesterol published by the American College of Cardiology (ACC)/American Heart Association (AHA) recommended against treating to a specific serum concentration of low-density lipoprotein cholesterol (LDL-C) and for treating patients according to their estimated cardiovascular (CV) risk.¹ These guidelines were in part based on two meta-analyses conducted by the Cholesterol Treatment Trialists' (CTT) Collaboration.^2,3 A meta-analysis published recently by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) performed a similar type of analysis for patients enrolled in trials of antihypertensive therapy in order to estimate the CV risk reduction for different subgroups of patients.⁴

Methods

The BPLTTC analyzed individual patient data from 11 trials that randomized 51,917 patients to treatment with placebo versus angiotensin-converting enzyme inhibitor (ACEI), placebo versus calcium channel blocker, or placebo versus diuretic; or to more versus less intensive treatment goals. Individual patient variables included age, sex, body mass index, systolic and diastolic blood pressure (BP), other BP treatment, smoking status, diabetes mellitus, and history of CV disease. A total of 1,526 CV events occurred in the cohort. The primary outcome was a composite of major fatal and non-fatal CV events that included stroke, coronary heart disease, heart failure, or CV death. Patients were divided into four subgroups of five-year CV risk (<11%, 11-15%, 15-21%, >21%) based on a risk prediction equation developed from the baseline BP and the CV risk rate in the placebo group.

Results

Pharmacologic BP treatment reduced the relative risk of CV events similarly in all four subgroups (p = 0.3). The absolute risk reduction increased in a linear fashion from the lowest to the highest risk quartile (p = 0.04 for trend). The authors estimated that treating 1,000 patients in each of the four groups for five years would prevent 14 CV events in the lowest risk quartile and 38 events in the highest risk quartile.

Conclusion

Patients at the highest risk for a CV event derived the greatest benefit from antihypertensive treatment in this large meta-analysis of individual patient data from selected randomized controlled trials.

Discussion

The meta-analysis by the BPLTTC provides a quantitative approach to CV risk estimation and to the effect of selected antihypertensive drugs on that risk. Among the strengths of this meta-analysis are the use of individual patient data to construct the baseline risk subgroups from patients assigned to placebo, the innovative use of carefully chosen formulas on which the risk estimates were based, the incorporation of all rather than selected CV events, and careful attention to the duration of the clinical trials that resulted in the development of five- rather than 10-year risk estimates. Since the criteria for entry into a clinical trial are necessarily restrictive, it is difficult to know how robust the risk prediction equations developed by BPLTTC will be when applied to a larger and more heterogeneous population of patients with hypertension. Based on the demographic characteristics of the cohort provided in the publication, several groups are either not represented in the cohort or are not included in the risk calculations. For example, the number of patients in the cohort who are less than 50 years old, have chronic kidney disease, or are of non-white race is not specified. In addition, values for circulating lipids were not included in the risk prediction models because they were missing from too many of the trials, further limiting the widespread application of this risk estimator.

Although hypertension is included in all CV risk calculators such as the one published recently by the ACC/ AHA for assessment of CV risk,⁵ there are currently no published, peer-reviewed risk estimators to assist clinicians in determining composite CV risk of hypertensive patients. Until the current publication, it was not possible to associate baseline CV risk estimates with the effects of pharmacological treatment using values from individual patients. However, recognition of the potential importance of basing treatment intensity on composite CV risk has been present in the hypertension literature for many years. It is perhaps most clearly illustrated in the European Society of Hypertension guidelines for hypertension management. A graphic in that document identifies risk categories based on both the extent of BP elevation and on the composite number of CV risk factors.⁶ The strength of the evidence on which that algorithm was based is not specified. Other recent guidelines have taken a less global approach to treatment and instead focus more on target-organ-specific subgroups, such as patients with diabetes or chronic kidney disease.^7,8

What are the implications for hypertensive patients in the U.S. if a risk stratification approach to treatment were to be adopted? Analysis of the National Health and Nutrition Examination Survey (NHANES) data from 1999-2012 revealed that 18.4% of Americans with hypertension, or 3.7 million people, have a low estimated 10-year coronary heart disease risk.⁹ In the BPLTTC study, 49.1% of the cohort fell into their lowest risk group, with five-year CV risk of <11%. Using these criteria, up to 10 million Americans with hypertension may have a five-year CV risk of <11%. One obvious question raised by these estimates is whether de-escalation of BP therapy in lower risk patients should be considered as a part of high-value care. On the other end of the spectrum, the highest risk patients from the BPLTTC study were older males who were more likely to smoke and have a history of CV disease, diabetes, high systolic BP, and low HDL. The BPLTTC risk estimates predict this high-risk subgroup, representing 10% of the NHANES population or 2.2 million people, would derive the greatest CV benefit from BP reduction. It remains to be seen whether a new risk calculator that incorporates the findings of this meta-analysis will be developed, validated, and made available to clinicians, or whether already-available CV risk calculators will be equally effective in risk stratifying hypertensive patients.

References

1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934.
2. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
3. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-81.
4. Sundstrom J, Arima H, Woodward M, et al. Blood pressure-lowering treatment based on cardiovascular risk: a meta-analysis of individual patient data. Lancet 2014;384:591-598.
5. Goff DC, Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-59.
6. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013;31:1281-1357.
7. Hackam DG, Quinn RR, Ravani P, et al. The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol 2013;29:528-42.
8. 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;311:507-20.
9. Egan BM, Li J, Hutchison FN, Ferdinand KC. Hypertension in the United States, 1999 to 2012: progress toward healthy people 2020 goals. Circulation 2014;130(19):1692-9.

Keywords: Algorithms, American Heart Association, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Blood Pressure, Body Mass Index, Calcium Channel Blockers, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Coronary Disease, Diabetes Mellitus, Diuretics, Heart Failure, Hypertension, Lipids, Lipoproteins, LDL, Moclobemide, Renal Insufficiency, Chronic, Risk, Risk Factors, Risk Reduction Behavior, Smoke, Smoking, Stroke, Primary Prevention

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