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Incremental effects of antihypertensive drugs: instrumental variable analysis

BMJ 2017; 359 doi: (Published 22 December 2017) Cite this as: BMJ 2017;359:j5542

To add Which one? Antihypertensive or Statins Drugs?

Markovitz AA, et al1 assessed the incremental effects of adding extra antihypertensive drugs from a new class to a patient's regimen. In instrumental variable models, the addition of an antihypertensive drug from a new class led to clinically important reductions in systolic blood pressure (-14.4 mm Hg) and fewer major cardiovascular events (absolute risk -6.2). Incremental reductions in systolic blood pressure remained large and similar in magnitude for patients already taking drugs from zero, one, two, or three or more drug classes. This finding was consistent across all subgroups of patients.

Patients with hypertension often require multiple antihypertensive drugs. Observational studies suggest that benefits diminish when additional antihypertensive drugs are prescribed.2,3 However, the current study challenges the view that the effects of antihypertensive drugs will diminish with each added drug class while increasing the adverse effects.

Physicians are now in chaos because of recent controversial clinical trials. Various strategies to reduce residual cardiovascular risk in hypertensive patients included treating BP to lower target goals and using different classes of antihypertensive medications, however still considerable residual risk remained. In contrast, controlling hypercholesterolemia in hypertensive patients by statins is very effective in reducing residual cardiovascular risk by 35% to 40%.4 Also, cross-talk between hypercholesterolemia and rennin angiotensin system (RAS) exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS blockers (one class of antihypertensive medications) demonstrate additive/synergistic effects on endothelial dysfunction and insulin resistance in addition to lowering cholesterol levels and blood pressure when compared with either monotherapy in patients.5,6 This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS blockers may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome, or obesity to prevent vascular risk.7-9

The American Heart Association and American College of Cardiology recently lowered the national blood pressure target from 140/90 mm Hg to 130/80 mm Hg for the general population, in a guideline endorsed by nine additional groups. The new guidelines mean that more than 100 million Americans now qualify for hypertension diagnosis and suggest that already diagnosed individuals be managed with more antihypertensive medications to reach a new target.

Questions have been raised, however, about which strategy is better. To add which one? Antihypertensive or statins drugs?

Funding: None, Disclosures: None

1. Markovitz AA, Mack JA, Nallamothu BK, Ayanian JZ, Ryan AM. Incremental effects of antihypertensive drugs: instrumental variable analysis. BMJ 2017;359:j5542.

2. Rana BK, Dhamija A, Panizzon MS. Imputing observed blood pressure for antihypertensive treatment: impact on population and genetic analyses. Am J Hypertens 2014;27:828-37.

3. Timbie JW, Hayward RA, Vijan S. Variation in the net benefit of aggressive cardiovascular risk factor control across the US population of patients with diabetes mellitus. Arch Intern Med 2010;170:1037-44.

4. Egan BM, Li J, Qanungo S, Wolfman TE. Blood pressure and cholesterol control in hypertensive hypercholesterolemic patients: National health and nutrition examination surveys 1988-2010. Circulation 2013;128:29-41.

5. Koh KK, Quon MJ, Han SH, et al. Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation 2004;110:3687-92.

6. Koh KK, Quon MJ, Han SH, et al. Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes. Hypertension 2005;45:1088-93.

7. Koh KK. Quon MJ. Targeting converging therapeutic pathways to overcome hypertension. Int J Cardiol 2009;132:297-9.

8. Lim S, Sakuma I, Quon MJ, Koh KK. Potentially important considerations in choosing specific statin treatments to reduce overall morbidity and mortality. Int J Cardiol 2013;167: 1696-1702.

9. Koh KK, Lim S, Choi H, et al. Combination pravastatin and valsartan treatment has additive beneficial effects to simultaneously improve both metabolic and cardiovascular phenotypes beyond that of monotherapy with either drug in patients with primary hypercholesterolemia. Diabetes 2013;62:3547-552.

Competing interests: No competing interests

03 January 2018
Kwang Kon KOH
Professor of Medicine
Department of Cardiovascular Medicine, Gachon University, Gil Medical Center
774 Beongil 21, Namdongdaero, Namdong-Gu