Combining ARBs, CCBs and Diuretics in controlling Resistant Hypertension in CV patients: Review

A significant increase in resistant hypertension (RH) has been documented in the last decade, with epidemiological data suggesting that the rise has doubled with 20–30% of hypertensive patients being diagnosed with RH (1,2). More alarming is the fact that RH has been linked to a 1.1–3-fold increase in the risk of cardiovascular events. (3,4)

Recent reports have revealed RH to be prevalent in 1 out of every 5 patients, with either at least three atherosclerotic risk factors or established disease. (5) Acknowledging the well-established etiology of atherosclerosis as both a cause and a consequence of coronary artery disease as well as hypertension (6), researchers worldwide are on the lookout for an optimized and standardized pharmacotherapy in managing such patients.

With the American Heart Association (7) acknowledging treatment-resistant hypertension as a priority area, an elaborate discussion analyzing the prevalence rates, the hypotheses explaining the association of RH and CVD, while summarizing on the best available treatment option is the need of the hour.

What statistics reveal: Quoting studies

In one of its kind study (8), where participants were segregated into 2 groups, in accordance to AHA definition; one group comprised of a systolic blood pressure >140 mm Hg despite concurrent use of 3 antihypertensive agents of different classes and those with blood pressure <140 mm Hg but controlled with 4 medications; researchers observed a 73% increase in primary outcome driven by a 58% increase in coronary heart disease death, an 82% increase in nonfatal myocardial infarction, and a 52% increase in stroke when compared with placebo in the first group. They further noted a 61% increase in the major coronary event, a 56% increase in any cardiovascular event, a 69% increase in any coronary event, a 98% increase in angina pectoris, and a 48% increase in coronary revascularization among the second group. Such results speak volumes of the high risk of developing major cardiovascular diseases among RH patients, if not treated in a timely.

Yet another recent report from the Cardiovascular Research Network found RH to be associated with an increased risk for the composite outcome of death, stroke, myocardial infarction, chronic kidney disease, and heart failure. (4)

RH and CVD: How are they linked?

In an interesting study, researchers have highlighted that the presence of cardiovascular-related comorbidities like heart failure and left ventricular hypertrophy (LVH), diabetes, history of stroke/transient ischemic attack (TIA), percutaneous coronary intervention (PCI), peripheral vascular disease (PVD), and renal insufficiency as among the strongest predictors of RH. (9) This affirms that RH and coronary artery disease exhibit a concomitant cause and effect inter-relationship. The study concluded that RH increased the risk of major cardiovascular events and all-cause mortality when compared with controlled hypertension, a fact that has been resonated in other notable studies. (7)

Though the exact cause of increased incidences of CAD among RH patients remains to be fully explored, RH patients likely have a greater BP burden over time, which if left untreated, leads to altered physiological mechanisms including increased rennin–angiotensin system stimulation and aldosterone production, increased arterial stiffness, and atherosclerotic diseases, thus aggravating the cardiovascular risk. (10,11)

Managing RH in CVD patients- The European Society of Cardiology guidelines (12) clearly states that the relationship between blood pressure (BP) and CV morbidity and mortality could be modified by the concomitance of other CV risk factors. Studies have affirmed that multidrug therapy is the treatment of choice in such cases, with Angiotensin-converting enzyme (ACE) inhibitors/Angiotensin II receptor blockers (ARBs) demonstrating consistent improvements in arterial stiffness parameters, novel Calcium channel blockers (CCBs) blocking activity on N/ T / L-type channels (causing further reductions in cardiovascular events and renal injury), and a diuretic working to reduce the volume overload. (13) Research shows that such combination therapies are not only directed at controlling hypertension, rather they provide an extensive cardioprotective potency and exhibit anti-ischemic properties. (13)

● Role of CCBs- Longer-acting Calcium Channel Blockers like Nifedipine act via peripheral vasodilation, reducing the elevated BP bioburden while providing adjunctive cardioprotective effect by decreasing heart rate and myocardial contractility. (14) Contrary to relatively shorter acting CCBs which can increase sympathetic activity and re-activate RAAS, Nifedipine has been extensively documented to be beneficial in RH with CAD.(14)

● Role of ARBs-According to ESH–ESC (15) and JNC guidelines(16), RAAS-inhibitors, in the form of ACEIs and ARBs, are among the first choice for RH in patients by their proven efficacy in cardiac protection, with additional renal protection.

Azilsartan Medoxomil (AZL-M) is the eighth approved member of ARBs which has a proven history of higher potency in reduction of in-office or ambulatory systolic BP when compared to other ARBs like olmesartan, valsartan, and candesartan. (17) The superiority of AZL-M in lowering BP during a 24 h period could be partially explained by its selective and tighter binding properties. Further, studies have shown beneficial effects of AZL-M regarding pro-atherosclerotic pathways, thus asserting its beneficial effects in CAD.(17)

Accumulating research highlights that the combination of AZL-M and chlorthalidone (CLD) was consistently more efficient than either combination of AZL-M / hydrochlorothiazide (HCTZ), olmesartan /HCTZ, or their monotherapies in controlling RH.(17)

● Role of diuretics- Patients with RH are vulnerable to multiple co-morbidities; renal insufficiency is one of the most common ones. With such a high association of CKD in such cases, taking care of the extracellular volume expansion (due to fluid and sodium retention) has to be given prime importance. Thiazide diuretics, especially chlorthalidone, have a longer antihypertensive effect than loop diuretics; however, they are less effective at low levels of GFR. A loop diuretic with a longer duration of action is preferred in patients with more advanced CKD (GFR<30 ml/min/1.73 m2), as well as in acute renal failure.(18)

The notable ALLHAT trial (19) showed that chlorthalidone reduced systolic BP more than either amlodipine or lisinopril, reaffirming the European and US guidelines on hypertension which recommend the use of thiazide diuretics as first-line therapy(20). Among the loop diuretics, Torsemide Combining ARBs, CCBs and Diuretics in controlling RH in CV patients: A Review, dosed once daily, is regarded to be better in cases of severe renal impairment with significantly low GFR. (21)

Highlighters

● To achieve the desired levels of BP in RH patients, an ACEI or ARB can be combined with a thiazide diuretic or loop diuretic, and, if necessary, a CCB can be added.

● The choice of diuretics is focused on the GFRs and stages of renal disease.

● With triple combination therapy being widely explored in recent researches, in-depth knowledge of updates by physicians can go a long way in tailoring the most appropriate customized pharmacotherapy based on individual needs and associated comorbidities.

Conclusion

With 1 in every 2 patients being diagnosed with uncontrolled blood pressure, RH is now being increasingly recognized as a distinct clinical entity among the medical fraternity. Navigating through the challenges faced by physicians in successfully treating RH with CVD, scientific evidence backs triple-drug therapy as the best-at-hand pharmacotherapy to date. As more research continues to focus and unveil the pros and cons of combination therapy in such difficult-to-manage high-risk groups, the interest in this challenging health condition is on an exponential rise among physicians.

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Resistant Hypertension, click HERE

References

1. Cushman WC, Ford CE, Cutler JA, Margolis KL, Davis BR, Grimm RH, et al. Success and predictors of blood pressure control in diverse North American settings: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J ClinHypertens (Greenwich). 2002; 4:393–404. [PubMed: 12461301]

2. Gupta AK, Nasothimiou EG, Chang CL, Sever PS, Dahlöf B, Poulter NR. ASCOT Investigators.Baseline predictors of resistant hypertension in the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT): a risk score to identify those at high-risk. J Hypertens. 2011; 29:2004–2013. [PubMed:21881528]

3. Pierdomenico SD, Lapenna D, Bucci A, Di Tommaso R, Di Mascio R, Manente BM, et al.Cardiovascular outcome in treated hypertensive patients with responder, masked, false resistant, and true resistant hypertension. Am J Hypertens. 2005; 18:1422–1428. [PubMed: 16280275]

4. Daugherty SL, Powers JD, Magid DJ, Tavel HM, Masoudi FA, Margolis KL, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation. 2012; 125:1635–1642.[PubMed: 22379110]

5. Tackling G, Borhade MB. Hypertensive Heart Disease. [Updated 2021 Jul 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539800/

6. Singh, R. B., Mengi, S. A., Xu, Y. J., Arneja, A. S., &Dhalla, N. S. (2002). Pathogenesis of atherosclerosis: A multifactorial process. Experimental and clinical cardiology, 7(1), 40–53.

7. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR, Egan BM, Flack JM, Gidding SS, Judd E, Lackland DT, Laffer CL, Newton-Cheh C, Smith SM, Taler SJ, Textor SC, Turan TN, White WB; on behalf of the American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72:e53–e90. DOI:10.1161/HYP.0000000000000084

8. Smith SM, Gong Y, Handberg E, Messerli FH, Bakris GL, Ahmed A, Bavry AA, Pepine CJ, Cooper-Dehoff RM. Predictors and outcomes of resistant hypertension among patients with coronary artery disease and hypertension. J Hypertens. 2014 Mar;32(3):635-43. doi: 10.1097/HJH.0000000000000051. PMID: 24299915; PMCID: PMC4118668.

9. Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith SC, Crowley K, et al. Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis.Eur Heart J. 2013; 34:1204–1214. [PubMed: 23144048]

10. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension:diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008; 51:1403–1419. [PubMed: 18391085]

11. Smith SM. Epidemiology, prognosis, and treatment of resistant hypertension. Pharmacotherapy.2013; 33:1071–1086. [PubMed: 23722533]

12. Piepoli, M. F., Hoes, A. W., Agewall, S., Albus, C., Brotons, C., Catapano, A. L., Cooney, M. T., Corrà, U., Cosyns, B., Deaton, C., Graham, I., Hall, M. S., Hobbs, F., Løchen, M. L., Löllgen, H., Marques-Vidal, P., Perk, J., Prescott, E., Redon, J., Richter, D. J., … ESC Scientific Document Group (2016). 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). European heart journal, 37(29), 2315–2381. Taddei S. Combination therapy in hypertension: what are the best options according to clinical pharmacology principles and controlled clinical trial evidence? Am J Cardiovasc Drugs. 2015 Jun;15(3):185-94. doi: 10.1007/s40256-015-0116-5. PMID: 25850749.

13. Ptinopoulou AG, Pikilidou MI, Lasaridis AN. The effect of antihypertensive drugs on chronic kidney disease: a comprehensive review. Hypertens Res. 2013 Feb;36(2):91-101. doi: 10.1038/hr.2012.157. Epub 2012 Oct 11. PMID: 23051659.

14. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Erdine S, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Lindholm LH, Viigimaa M, Adamopoulos S, Bertomeu V, Clement D, Farsang C, Gaita D, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O'Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten PA, Waeber B, Williams B. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105–1187.

15. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, IzzoJr JL, Jones DW, Materson BJ, Oparil S, Wright Jr JT, Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–2572.

16. Georgiopoulos G, Katsi V, Oikonomou D, Vamvakou G, Koutli E, Laina A, Tsioufis C, Nihoyannopoulos P, Tousoulis D. Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study. Front Pharmacol. 2016 Aug 3;7:235. doi: 10.3389/fphar.2016.00235. PMID: 27536242; PMCID: PMC4971108.

17. K/DOQI. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43: S1–S290.

18. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–2997.

19. Wright JM, Musini VM. First-line drugs for hypertension. Cochrane Database Syst Rev 2009; 8: CD001841.

20. Moser M, Cushman W, Handler J. Resistant or difficult-to-treat hypertension. J ClinHypertens (Greenwich) 2006; 8: 434–440