Antihypertensive Treatment Update

Antihypertensive Treatment Update
Sarah Shockley, PharmD, Fairview

Background: For years, there has been very little guidance from the hypertension guidelines about the optimal first-line agent to treat high blood pressure (BP), as well as timing of medication dosing. The 2017 ACC/AHA High Blood Pressure Clinical Practice Guidelines suggest that patients with BP 130-139/80-89 mmHg with an ASCVD risk >10%, or >140/90 mmHg irrespective of ASCVD risk should receive BP-lowering medication. First-line agents include thiazide or thiazide-type diuretics, ACE inhibitors, ARBs, CCB-dihydropyridines, and CCB-nondihydropyridines. For patients without comorbidities, these are recommended with equal weight. In patients with comorbidities, chlorthalidone is preferred in cardiovascular disease (CVD), ACE inhibitors and ARBs are preferred in chronic kidney disease (CKD), CCB-nondihydropyridines should be avoided in heart failure (HF) and CCB-dihydropyridines should be used cautiously in HF. 

In comparison, the 2014 JNC8 Guidelines recommend treating to a goal of <150/90 mmHg for patients >60 years of age, and <140/90 mmHg for patients <60 years of age. The JNC8 supports initiating any of the following drug treatments with equal weight in the nonblack hypertensive population: ACE inhibitors, ARBs, any CCB, or thiazide and thiazide-type diuretics, which is similar to the 2017 ACC/AHA guideline. In the black hypertensive population, including those with diabetes (DM), any CCB, or thiazide and thiazide-type diuretics are recommended as initial therapy. They also recommend initiating therapy with an ACE inhibitor or ARB in persons with CKD to improve kidney outcomes.

Evidence: In a new comprehensive analysis, outcomes in a new-drug user cohort across 4.9 million patients were explored. Researchers used data from a global network of six administrative claims and three electronic health record databases to estimate the relative risks of three primary endpoints (acute myocardial infarction (MI), hospitalization for HF, and stroke), six secondary effectiveness endpoints, and 46 safety outcomes when comparing all first-line classes of drug therapy. Most estimates revealed no difference in effectiveness between classes, however thiazide and thiazide-type diuretics showed better outcomes for primary endpoints than ACE inhibitors: acute MI (0.84, [95% CI 0.75–0.95]), hospitalization for HF (0.83 [95% CI 0.74–0.95]), and stroke (0.83 [95% CI 0.74–0.95]). In 16 different statistically significant safety outcomes including mortality, gastro-intestinal side effects, and renal disorders, thiazide and thiazide-type diuretics were favored over ACE inhibitors. The CCB-nondihydropyridines were significantly inferior to the other classes.

Additionally, the Hygia Chronotherapy Trial provides some evidence that taking at least one BP medication at bedtime can improve BP lowering and CVD outcomes. Over 19,000 patients were studied, one group administered antihypertensive medications at bedtime and another upon awakening. Patients who took antihypertensive medications at bedtime had significantly lower hazard ratios for asleep systolic blood pressure (SBP) mean, sleep-time relative SBP decline, and primary CVD outcome (0.55 [95% CI 0.50-0.61], P < 0.001). This statistically significant outcome was observed across all cases (CVD death (0.44 [95% CI 0.34-0.56]), MI (0.66 [95% CI 0.52-0.84]), coronary revascularization (0.60 [95% CI 0.47-0.75]), HF (0.58 [95% CI 0.49-0.70]), and stroke (0.51 [95% CI 0.41-0.63]), even when adjusted for influential characteristics (age, sex, type 2 diabetes, CKD, smoking, HDL cholesterol, etc).

Clinical Impact: Based on the information provided in these new trials, evidence supports the use of thiazide or thiazide-type diuretics as first-line therapy for patients without comorbidities, ACE inhibitors or ARBs for patients with CKD, and the avoidance of all CCBs as first-line therapy based on safety profiles. Additionally, once the patient is on more than one hypertensive agent, at least one of those agents should be moved to bedtime as tolerated to improve BP-lowering and reduce risk of CVD. We will have to wait to see how these trials are considered for the next iteration of hypertension guidelines.

Summary: The current guidelines recommend any drug in five different pharmaceutical classes as first-line treatment for hypertension. A recent study published in The Lancet shakes up the guidelines with new recommendations for first-line agents. 


  1. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71:e127-e248.

  2. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults. JAMA. 2014;311(5):507-520.

  3. Suchard MA, Schuemie MJ, Krumholz HM, et al. Comprehensive comparative effectiveness and safety of first-line antihypertensive drug classes: a systematic, multinational, large-scale analysis. Lancet. 2019 Nov 16;394(10211):1816-1826.

  4. Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial. Eur Heart J. 2019 Oct 22. pii: ehz754.