Synthesis: Pharmacological Management of Hypertension


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A direct comparison of recommendations presented in the above guidelines for the pharmacological management of hypertension is provided. It should be noted that the guidelines differ somewhat in scope. Besides addressing pharmacotherapy, for example, the VA/DoD guideline also provides recommendations for the screening, diagnosis, measurement and non-pharmacological management of hypertension. These topics, however, are beyond the scope of this synthesis. In addition, the focus of the ACP/AAFP guideline is the treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets. As such, the developer does not offer specific pharmacotherapy recommendations.

Areas of Agreement

Diastolic Blood Pressure (DBP) Treatment Thresholds and Goals

In patients aged 30 or older, VA/DoD and JNC 8 agree that pharmacologic therapy should be offered/initiated at DBP ≥90 mmHg, and that patients should be treated to a goal of <90 mmHg. Citing a lack of evidence in younger adults, the guideline developers each offer a weak recommendation for the use of the same treatment threshold and goal in adults 18 to 29 years. There are no outcome studies published evaluating patients younger than age 30, VA/DoD remarks, so an appropriate threshold for initiating antihypertensive pharmacologic treatment is not clear. In this younger population, it may be appropriate to recommend a three to six month period of therapeutic lifestyle modification prior to offering medication management when DBP is ≥90 mmHg, adds the developer. The JNC 8 panel also acknowledges the lack of good- or fair-quality RCTs that assessed the benefits of treating elevated DBP on health outcomes in adults younger than 30 years. In the absence of such evidence, the Panel concluded that the DBP threshold and goal should be the same as in adults 30 through 59 years of age. ACP/AAFP concluded that the evidence was insufficient to determine the benefit of treating diastolic hypertension in the absence of systolic hypertension. Most trials assessed treatment outcomes based on SBP, the guideline states, and no trials included patients with a mean DBP >90 mmHg and a mean SBP <140 mmHg.

Patients with Chronic Kidney Disease (CKD)

VA/DoD and the JNC 8 Panel agree that treatment of patients with hypertension and CKD should include an ACEI or ARB to improve kidney outcomes and that these patients should be treated to a goal BP of <140/90 mmHg. The VA/DoD expands upon this guidance for African Americans with hypertension and stage 1-3 CKD, by suggesting a combination of a thiazide-type diuretic (for cardiovascular protection) in addition to either an ACEI or ARB. In line with the guidance provided by VA/DoD and the JNC 8 Panel, the ACP/AAFP guideline offers a weak recommendation based on low-quality evidence to consider treating some adults 60 years or older at high cardiovascular risk—which generally includes older persons with CKD with an estimated GFR <45 mL/min/1.73 m2—to a target SBP of <140 mmHg. ACP/AAFP adds that this decision should be based on individualized assessment, and clinicians should select the treatment goals based on a periodic discussion of the benefits and harms of specific blood pressure targets with patients.

African American Patients

For the general African American population, including those with diabetes, VA/DoD and the JNC 8 Panel agree that monotherapy with an ACEI or ARB is not recommended, and that initial antihypertensive treatment should include a thiazide-type diuretic or CCB. Noting a potential conflict between their recommendation to use an ACEI or ARB in those with CKD and hypertension and the subsequent recommendation to use a diuretic or CCB in African Americans, JNC 8 clarifies that in African American patients with CKD and proteinuria, an ACEI or ARB is recommended as initial therapy because of the higher likelihood of progression to end-stage renal disease. In African American patients with CKD but without proteinuria, the choice for initial therapy is less clear and includes a thiazide-type diuretic, CCB, ACEI, or ARB. If an ACEI or ARB is not used as the initial drug, then an ACEI or ARB can be added as a second-line drug if necessary to achieve goal BP. Because the majority of patients with CKD and hypertension will require more than 1 drug to achieve goal BP, it is anticipated that an ACEI or ARB will be used either as initial therapy or as second-line therapy in addition to a diuretic or CCB in African American patients with CKD.

Patients with Refractory Hypertension

Both VA/DoD and JNC 8 recommend considering other drug classes for patients who do not tolerate or whose blood pressure is not adequately controlled with triple therapy (i.e., thiazide-type diuretics, ACEI or ARB, and CCBs). Drug classes to consider include aldosterone receptor antagonists (e.g., spironolactone); peripherally acting antiadrenergic agents (e.g., reserpine); direct vasodilators (e.g., hydralazine); dual alpha-beta adrenergic blockers (e.g., carvedilol); and centrally acting antiadrenergic drugs (e.g., clonidine). The ACP/AAFP guideline does not address pharmacologic treatment of refractory hypertension.

Areas of Difference

Systolic Blood Pressure (SBP) Treatment Thresholds and Goals

The guideline developers endorse different SBP pharmacologic treatment thresholds in hypertensive patients aged 60 years or older. On the basis of evidence for reduction in clinical events from several RCTs (SHEP, HYVET, EWPHE), VA/DoD makes a strong recommendation for offering pharmacologic treatment at SBP ≥160 mmHg. For those patients 60 years or older with SBP <160 mmHg, VA/DoD suggests considering pharmacologic treatment using a shared decision-making model.

In contrast, the JNC 8 Panel strongly recommends a pharmacologic treatment threshold of SBP ≥150 mmHg in this patient population. On the basis of high-quality evidence, the ACP/AAFP guideline also makes a strong recommendation for initiating treatment (pharmacologic or nonpharmacologic) in adults aged 60 years or older with SBP persistently ≥150 mmHg in order to reduce the risk for mortality, stroke, and cardiac events. The guideline emphasizes that clinicians select the treatment goals based on a periodic discussion of the benefits and harms of specific blood pressure targets with the patient. All of the guideline developers agree, however, that average-risk hypertensive patients in this age group should be treated to a goal SBP of <150 mmHg.

The ACP/AAFP guideline also offers weak recommendations for treating selected higher risk adults aged 60 years or older to a lower target SBP than those at average risk. Specifically, the developers recommend that clinicians consider initiating or intensifying pharmacologic treatment to achieve a target SBP of <140 mmHg in patients with a history of stroke or TIA, in order to reduce the risk for recurrent stroke, as well as in some patients determined to be at high cardiovascular risk based on individualized assessment, to reduce the risk for stroke or cardiac events. The guideline developer notes that, generally, increased cardiovascular risk includes persons with known vascular disease, most patients with diabetes, older persons with CKD and estimated GFR <45 mL/min/1.73 m2, those with metabolic syndrome, and older persons (for example, age ≥75 years). ACP/AAFP emphasizes, however, that clinicians should select the treatment goals for all adults aged 60 years or older based on a periodic discussion of the benefits and harms of specific BP targets with the patient.

In the general population younger than 60 years, VA/DoD conditionally recommends (suggests) the same SBP treatment initiation threshold (≥160 mmHg) and treatment goal (SBP <150 mmHg) recommended for adults 60 years or older. The developer notes the only study in the evidence base that enrolled patients younger than age 60 with SBP of 150–179 mmHg found no difference in major cardiovascular events or mortality between the control and active treatment groups. Thus the recommendations for SBP thresholds for people less than 60 years were based on outcomes other than surrogate outcomes, such as blood pressure. The VA/DoD also explains the recommendation for suggested treatment at age less than 60 years is based on potential benefit for reduction in cardiovascular events and low patient burden associated with pharmacologic treatment. Citing expert opinion, JNC 8 offers different guidance for patients in this age group. While there is high-quality evidence to support a specific SBP threshold and goal for persons aged 60 years or older, the Panel found insufficient evidence from good- or fair-quality RCTs to support a specific SBP threshold or goal for persons younger than 60 years. In the absence of such evidence, JNC 8 recommends a treatment threshold of SBP ≥140mmHg and treatment goal of SBP <140 mmHg based on several factors, including the absence of RCTs comparing the current SBP standard of 140 mmHg with another higher or lower standard in this age group. The ACP/AAFP guideline does not address adults younger than 60 years.

Diabetic Patients

VA/DoD and the JNC 8 both cite moderate-quality evidence from three RCTs (SHEP, Syst-Eur, and UKPDS) that treatment to an SBP goal of <150 mmHg improves major cardiovascular and cerebrovascular outcomes and lowers mortality in adults with diabetes and hypertension. VA/DoD makes a strong recommendation for treating to a BP goal of <150/85 mmHg in this patient population. For diabetic patients who can tolerate antihypertensive drugs, the developer suggests a lower goal SBP of <140 mmHg. Support for this recommendation comes from two trials. The ACCORD-BP trial demonstrated that the control group (goal SBP <140 mmHg) had similar cardiovascular outcomes but fewer serious adverse events than the lower SBP goal group. The ADVANCE trial showed that mortality was reduced with a combination of a thiazide-type diuretic and an ACEI to lower blood pressure in persons with diabetes. Although there was not an SBP goal, the mean achieved SBP of 135 mmHg is consistent with an SBP goal of <140 mmHg. Both developers cite the absence of RCTs addressing whether treatment to an SBP goal of <140 mmHg compared with a higher goal (e.g., <150 mmHg) improves health outcomes in adults with diabetes and hypertension. In the absence of such evidence, JNC 8 recommends treating to a BP goal of <140/90 mmHg in this population based on expert opinion, consistent with the BP goals for the general population younger than 60 years with hypertension. The JNC 8 Panel did not consider the ADVANCE trial because it did not meet their inclusion criteria. The ACP/AAFP guideline offers a weak recommendation for treating some adults, based on individualized assessment, 60 years or older at high cardiovascular risk—which includes most patients with diabetes—to a target SBP of <140 mmHg in order to reduce the risk for stroke or cardiac events.

Initial Pharmacological Therapy

VA/DoD makes a strong recommendation for the first-line use of thiazide-type diuretics. The developer explains that, similar to past guidelines, evidence supporting this recommendation is based mainly on placebo-controlled outcome trials with thiazide-type diuretics as the basis of therapy, as well as results from the ALLHAT trial. VA/DoD remarks on the significance of this latter trial to VA/DoD providers due to the >7,000 Veterans included in the study. The developer also considered newer evidence from the ACCOMPLISH study favoring combination therapy with an ACEI/CCB over an ACEI/thiazide-type diuretic. Although ACCOMPLISH weakened the strength of this recommendation, adds VA/DoD, there remains strong evidence to support the use of thiazide-type diuretics as first-line therapy. With regard to selection of a specific agent in this class, the developer suggests chlorthalidone or indapamide over hydrochlorothiazide.

In contrast, JNC 8 makes a moderate recommendation for the use of any of the following classes of drugs for the initial treatment of the nonblack population with hypertension: thiazide-type diuretics; CCBs; ACEIs or ARBs. According to the Panel, each of these four drug classes yielded comparable effects on overall mortality and cardiovascular, cerebrovascular, and kidney outcomes, with the exception of heart failure. Initial treatment with a thiazide-type diuretic was more effective than a CCB or ACEI, and an ACEI was more effective than a CCB in improving heart failure outcomes. While the Panel recognized that improved heart failure outcomes warrants consideration when selecting an initial drug therapy for hypertension, this finding was not compelling enough within the context of the overall body of evidence to preclude the use of the other drug classes for initial therapy.

The purpose of the ACP/AAFP guideline is to provide recommendations based on the benefits and harms of higher (<150 mmHg) versus lower (≤140 mmHg) SBP targets in adults age 60 or older. As such, the co-developers do not make specific recommendations for pharmacotherapy, but cite thiazide-type diuretics, ACEIs, ARBs, CCBs, and beta-blockers as effective pharmacologic options.

Combination Pharmacologic Therapy

VA/DoD and the JNC 8 Panel acknowledge that more than one antihypertensive drug is often needed to achieve BP control. With regard to initiation of combination therapy, if goal BP is not reached within one month of treatment, JNC 8 recommends increasing the dose of the initial drug or adding a second drug from one of the four classes recommended as first-line therapy (thiazide-type diuretic, CCB, ACEI, or ARB). VA/DoD suggests initiating combination therapy for patients with a baseline SBP of >20 mmHg or DBP of >10 mmHg above the patient’s goal. VA/DoD recommends ACEIs or ARBs (not concurrently) and long-acting dihydropyridine CCBs as appropriate alternatives for patients who cannot tolerate thiazide-type diuretics, as supplementary therapies for patients who do not reach their hypertensive goals, or for those starting on combination therapy. JNC 8 and VA/DoD agree that, if goal BP cannot be achieved with two drugs, a third may be added. The ACP/AAFP guideline does not address combination pharmacologic therapy.

AAFP, American Academy of Family Physicians

ACCOMPLISH, Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension

ACCORD-BP, Action to Control Cardiovascular Risk in Diabetes blood pressure trial

ACEI, angiotensin-converting enzyme inhibitor

ACP, American College of Physicians

ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation

ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial

ARB, angiotensin receptor blocker

ARR, absolute risk reduction

BP, blood pressure

CCB, calcium channel blocker

CI, confidence interval

CPG, clinical practice guideline

CKD, chronic kidney disease

DASH, Dietary Approaches to Stop Hypertension

DBP, diastolic blood pressure

EWPHE, European Working Party on High Blood Pressure in the Elderly

GFR, glomerular filtration rate

HTN, hypertension

HYVET, Hypertension in the Very Elderly Trial

JNC 8, Eighth Joint National Committee

NHLBI, National Heart, Lung, and Blood Institute

RCT, randomized controlled trial

RR, relative risk

SBP, systolic blood pressure

SHEP, Systolic Hypertension in the Elderly Program

SPRINT, Systolic Blood Pressure Intervention Trial

Syst-Eur, Systolic Hypertension in Europe Trial

TIA, transient ischemic attack

UKPDS, UK Prospective Diabetes Study

VA/DoD, Department of Veterans Affairs/Department of Defense