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Adding more antihypertensive drug classes leads to large reductions in SBP, major CV events

Stephen Padilla
05 Jan 2018

The addition of an antihypertensive drug from a new class to a patient’s regimen results in huge decreases in systolic blood pressure (SBP) and major cardiovascular (CV) events among those at high risk for CV events but without diabetes, suggests a recent study. Its effects on SBP remain large and similar in magnitude across all levels of baseline drug use and all subgroups of patients.

“Our results challenge the view that adding antihypertensive drugs will result in progressively diminishing effects on BP and CV events,” researchers said. [Am J Hypertens 2014;27:828-837; Arch Intern Med 2010;170:1037-1044; Health Serv Res 2010;45:437-456; J Am Board Fam Med 2010;23:371-375; N Engl J Med 2015;372:447-455]

Based on standard multivariable models unadjusted for confounding by indication, adding a new antihypertensive drug class correlated with modestly lower SBP (‒1.3 mm Hg; 95 percent CI, ‒1.6 to ‒1.0) and no change in major CV events (absolute risk of events per 1,000 patient-years, 0.5; ‒1.5 to 2.3). [BMJ 2017;359:j5542]

On the other hand, instrumental variable models showed better outcomes, with the addition of a new antihypertensive drug class resulting in clinically significant reductions in SBP (‒14.4 mm Hg; ‒15. 6 to ‒13.3) and fewer major CV events (absolute risk, ‒6.2; ‒10.9 to ‒1.3).

These reductions in SBP persisted for patients taking drugs from zero, one, two, or three or more drug classes, and this effect was consistent across all subgroups of patients. Furthermore, the addition of an antihypertensive drug from a new class did not lead to significant differences in serious adverse events in either standard or instrumental variable models.

“Collectively, these findings suggest that antihypertensive drugs can be used to lower BP effectively with the addition of a first, second, third, or fourth class of drug or more to a patient’s regimen,” said researchers, adding that the findings also provide more rigorous nuanced insight into optimal hypertension management.

Two competing models were offered to challenge the view that adding antihypertensive drug classes would led to progressively smaller reductions in BP: additive effects and synergistic effects. [BMJ 2003;326:1427; J Hum Hypertens 1998;12:761-763]

“Meta-analyses of clinical trials comparing dual vs monotherapy have found either additive or diminishing effects, while safety and efficacy trials of some specific triple combination therapies have found short-term effects that are less than additive,” researchers noted. [BMJ 2003;326:1427; Am J Med 2009;122:290-300; Am J Hypertens 2005;18:935-942; Hypertension 2009;54:32-39;  J Am Soc Hypertens 2011;5:102-113; J Clin Hypertens (Greenwich) 2010;12:869-878; Clin Ther 2010;32:1252-1269]

In this study, researchers conducted an instrumental variable analysis of data from SPRINT (Systolic Blood Pressure Intervention Trial). Randomization status was used as the instrumental variable to account for confounding by indication, when treatment seem less effective if they are administered to sicker patients.

Randomization status of patients (n=9,092) was either intensive (SBP target, <120 mm Hg) or standard (SBP target, <140 mm Hg) treatment. Results were then compared between instrumental variable models and standard multivariable models. SBP, major CV events, and serious adverse events were the main outcome measures.

“Future research on this issue should focus on developing experimental evidence on how the strong additive reductions in BP observed in our study could translate to patient benefit and harm,” researchers said.

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