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Editor's Note: Commentary based on Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. J Am Coll Cardiol 2015;65:1998-2038.

Background

Guidelines published by American College of Cardiology (ACC)/American Heart Association (AHA) in 2007¹ recommended target blood pressures (BP) be <130/80 mm Hg for patients with high coronary artery disease (CAD) risk, or CAD. Updated guidelines in 2015² recommend increased BP targets: <150/90 mm Hg for patients >80 years old, <140/90 for patients with CAD, acute coronary syndrome (ACS), and heart failure, and <130/80 for "some individuals with CAD," myocardial infarction (MI) or stroke.

Getting From <130/80 to <140/90 mm Hg

There are currently no Class I recommendations for target BP based on data from randomized controlled trials (RCTs). The 2007 guidelines cited the intravascular ultrasound substudy of the Comparison of Amlodipine Versus Enalapril to Limit Occurrences of Thrombosis (CAMELOT) trial³ in making the recommended target BP <130/80 mm Hg. This substudy enrolled mostly normotensive subjects with CAD and randomized them to receive amlodipine, enalapril, or placebo for two years. A reduction in coronary atheroma volume at a treated systolic BP (systolic BP [SBP]) <120 mm Hg was noted, but no change in volume with SBP of 120 to 140 mm Hg.

Since 2007, one primary and one secondary prevention RCT have found no significant reduction in composite cardiovascular events with lower BP targets. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial⁴ randomized 4,733 patients with type 2 diabetes to an intensive target SBP <120 mm Hg or a standard SBP target <140 mm Hg. There was no significant difference in the composite primary outcome of MI, stroke, or cardiovascular death between groups. Only stroke risk was significantly reduced in the intensive group in a pre-specified secondary analysis. Intensive treatment resulted in increased adverse events, including hypotension, bradycardia, hyperkalemia, and elevated serum creatinine.

The Secondary Prevention of Small Subcortical Strokes Trial (SPS3)⁵ randomized 3,020 patients with recent lacunar strokes to an intensive target SBP <130 mm Hg or a standard SBP target 130-149 mm Hg. There was no significant difference in the primary outcome of all strokes between the two groups, nor in secondary outcomes of MI, hospitalization for vascular events, or death. Targeting SBP <130 mm Hg significantly reduced intracerebral hemorrhage without reducing other stroke types. Adverse events were not different between the two groups, although renal events were not reported.

Both ACCORD and SPS3 had lower-than-expected event rates. Neither study found a significant reduction in MI or cardiovascular death with intensive SBP targets. On average, patients in these trials required 0.6 (SPS3) to 1.1 (ACCORD) more medications to achieve intensive BP targets. The reduction in all strokes found in ACCORD, but not in SPS3, may have been due to a lower achieved SBP in the intensive arm of ACCORD (119 mm Hg) than in SPS3 (127 mm Hg).

It is possible that patients with diabetes or with prior lacunar strokes have different baseline risk than patients without either but who have other cardiovascular risk factors. The Systolic Blood Pressure Intervention Trial (SPRINT)⁶ is an ongoing U.S. National Institutes of Health (NIH)-funded trial which has randomized 9,361 patients without diabetes or prior stroke to intensive versus standard control groups similar to ACCORD. The results are expected within the next few years.

BP Targets: One Size Fits Most?

Orthostatic hypotension (OH) may play a crucial deciding factor in determining BP targets for selected patients. An analysis of baseline data from the Captopril Prevention Project (CAPP) trial⁷ compared patients without OH to those with systolic OH, diastolic OH, and combined OH. After risk adjustment, systolic OH and combined OH were each associated with increased risk of stroke compared to no OH (hazard ratio [HR] 1.48 and 1.53, respectively). Diastolic OH was associated with increased risk of MI compared to no OH (HR 2.04).

In the future, advances in personalized medicine and genomics⁸ may permit treatment decisions based on cardiovascular phenotype, using office, home, or 24-hour BP.⁹ For example, patients with severely elevated BP have higher baseline cardiovascular risk than patients with moderately elevated BP.¹⁰ Patients with diastolic hypertension exhibit different cardiovascular risk when compared to patients with isolated systolic hypertension or those with systolic-diastolic hypertension.¹¹ Circadian BP patterns may also predict different cardiovascular risk when those with non-dipping, early morning surge and extreme dipping patterns are compared with dippers.⁹ Age also plays a role since older patients are more likely to have isolated systolic hypertension from arterial stiffness, lower diastolic BP (DBP), and increased risk of OH.

Which Patients Should Be Treated to Which Target?

In the absence of Class I recommendations, a prudent strategy might be as follows:

1. For patients with CAD under age 80 years, first target BP <140/90 mm Hg.
2. For patients with CAD tolerating on-treatment BP <130/80 mm Hg, continue current therapy.
3. For patients with CAD tolerating BP <140/90 mm Hg without OH, or worsening renal function or coronary ischemia, consider lowering BP to <130/80 mm Hg.
4. For patients with CAD with personal or family history of hemorrhagic stroke, consider lowering BP to <130/80 mm Hg.
5. For patients with CAD at especially high cardiovascular risk, consider obtaining 24-hour BP to assess circadian BP pattern.
6. For patients with CAD with OH or over age 80, target a higher BP.
7. For patients with CAD with wide pulse pressures and/or low DBP (<70 mm Hg), use caution in lowering BP due to possible "J-curve" phenomenon.

Conclusions

Recent guidelines from ACC/AHA recommend treating most CAD patients to a target BP <140/90 mm Hg, but in the absence of Class I evidence from RCTs, they provide more flexibility in establishing a BP goal for each patient based the BP phenotype, personal and family history, and comorbidities. Lower BP goals should be reserved for patients at increased risk of cardiovascular events who are tolerating BP-lowering therapy. Patients should be assessed for OH, which is an independent risk factor for cardiovascular events. Future research directions should evaluate personalized approaches to BP targets that take into account the patient's baseline cardiovascular risk in addition to their particular BP phenotype and comorbidities.

References

1. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation 2007;115:2761-88.
2. Rosendorff C, Lackland DT, Allison M, et al. Treatment of hypertension in patients with coronary artery disease: a scientific statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. J Am Coll Cardiol 2015;65:1998-2038.
3. Sipahi I, Tuzcu EM, Schoenhagen P, et al. Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis. J Am Coll Cardiol 2006;48:833-8.
4. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85.
5. Benavente OR, Coffey CS, Conwit R, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet 2013;382:507-15.
6. Ambrosius WT, Sink KM, Foy CG, et al. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT). Clin Trials 2014;11:532-46.
7. Fedorowski A, Wahlstrand B, Hedner T, Melander O. Systolic and diastolic component of orthostatic hypotension and cardiovascular events in hypertensive patients: the Captopril Prevention Project. J Hypertens 2014;32:75-81.
8. Tragante V, Barnes MR, Ganesh SK, et al. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. Am J Hum Genet 2014;94:349-60.
9. Li Y, Wei FF, Thijs L, et al. Ambulatory hypertension subtypes and 24-hour systolic and diastolic blood pressure as distinct outcome predictors in 8341 untreated people recruited from 12 populations. Circulation 2014;130:466-74.
10. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. 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;360:1903-13.
11. Verdecchia P, Schillaci G, Reboldi G, Franklin SS, Porcellati C. Different prognostic impact of 24-hour mean blood pressure and pulse pressure on stroke and coronary artery disease in essential hypertension. Circulation 2001;103:2579-84.

Keywords: Acute Coronary Syndrome, Amlodipine, Blood Pressure, Blood Pressure Determination, Bradycardia, Captopril, Cardiovascular Diseases, Cerebral Hemorrhage, Comorbidity, Coronary Artery Disease, Creatinine, Diabetes Mellitus, Type 2, Diastole, Enalapril, Genomics, Hyperkalemia, Hypertension, Hypotension, Precision Medicine, Myocardial Infarction, Phenotype, Plaque, Atherosclerotic, Risk Adjustment, Risk Factors, Secondary Prevention, Stroke, Lacunar, Systole, Thrombosis, Vascular Stiffness, Primary Prevention

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