International Journal of Biological & Medical Research

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Int J Biol Med Res. 2014; 5(3): 4414-4420 Int J Biol Med Res www.biomedscidirect.

com BioMedSciDirect Publications International Journal of BIOLOGICAL AND MEDICAL RESEARCH Review Article Combination Therapy in Managing Hypertension-An Overview Saif Ul Islam MD, R.

1 Int J Biol Med Res. 2014; 5(3): Int J Biol Med Res Contents lists available at BioMedSciDirect Publications International Journal of Biological & Medical Research Journal homepage: BioMedSciDirect Publications International Journal of BIOLOGICAL AND MEDICAL RESEARCH Review Article Combination Therapy in Managing Hypertension-An Overview Saif Ul Islam MD, R.PH 2169 Peakview Ave Sacrmento, CA.95835, United States ARTICLE INFO ABSTRACT Keywords: Hypertension Maintaining blood pressure Renin-Angiotensin-Aldosterone Hypertension is a condition that involves multiple body organs and physiological systems. Maintaining blood pressure (BP) by using one class of drugs that affect one or two systems usually have inadequate response and result in a compensatory or counter- regulatory response from others to blunt the targeted effect of individual drug. For example, starting with diuretics result in initially decrease in intravascular volume, this trigger Renin-AngiotensinAldosterone System which cause vaso constriction and salt retention. In most cases monotherapy failed to achieve the goal and results in various side effects because of high dosing of individual drug (2). Starting with low dose combination therapy of two or more drugs affecting multiple physiologic systems and having additive effects may result in better control of BP with less side effects (2, 6). It is also emphasized that available data show that combination therapy is more effective and has achieved targeted BP earlier then monotherapy (2, 7). It is concluded from the data that about 70-75% hypertensive patients require combination therapy. c Copyright 2010 BioMedSciDirect Publications IJBMR -ISSN: 0976:6685. All rights reserved. 1. Introduction Hypertension: Hypertension is a constant elevation of systolic pressure above 140 and diastolic pressure above 80 or both. According to JNC classification, normal blood pressure in an adult is less than 120/80, pre-hypertension /80-89, stage 1 hypertension /90-99 and stage 2 when systolic BP > 160 or diastolic BP >100. Epidemiology Approximately 65 million people in America and 970 million people around the world have hypertension (1). Majority of the people are unaware of this hypertension issue. It is more common in developing countries. Among the patients who are being treated for hypertension, only 34% have adequately controlled BP and 70% of these patients require combination of two or more drugs to control Pathophysiology : Pathophysiology of hypertension is a complex field and involves multiple organs and physiologic systems. Approximately 90% of hypertension cases are idiopathic or have no cause, and the rest of the * Corresponding Author : Saif Ul Islam MD, R.PH 2169 Peakview Ave Sacrmento, CA United States saif_1104@yahoo.com c Copyright 2010 BioMedSciDirect Publications. All rights reserved. Human body maintains BP with several mechanisms, which are interrelated and affect each other in various ways. Some of the known physiological systems involved in maintaining BP in the human body includes Na-K pumps, CVS, kidney, sympathetic and RAAS system, hormones like thyroid and testosterone, vasodilators like nitric oxide and bradykinin and several others. This underscores the importance of controlling multiple pathways to achieve the target goal in individual patient. Monotherapy vs Combination Therapy The purpose of controlling BP is to avoid cardiovascular events such as stroke, myocardial infarction, CAD, and kidney failure (2). Framingham and other studies have shown that decreasing BP has positive correlation in decreasing the risk of cardiac events. Hypertension itself is a modifiable factor of stroke. JNC guideline about controlling BP is to start mono therapy with thiazide diuretic, calcium channel blocker or ACEI/ARB or start combination therapy, if there is an elevation systolic BP of 20 and 10mm Hg diastolic BP above the target goal (3). Theoretically, blocking multiple physiologic pathways with low-dose combination therapy should give better and faster outcome with lesser side effects. It is the same strategy that is used in oncology where multiple drugs are used to achieve the goal with fewer side effects. Several studies have shown better result with combination therapy vs. mono therapy (5, 11). In a meta-analysis study of 42 trials, combination therapy with two different classes was five times more effective then increasing to dose of a single agent (26).

2 4415 There are several classes of drugs available for hypertension. Choosing from different classes that give additive effects with fewer side effects required thorough understanding of these classes. For example in the class of diuretics, most commonly used drug is HCTZ, which is thiazide diuretic. It is highly unlikely that in a low dose, it will decrease the BP to the target value. Moderately increasing the dose will result in increase of side effects, which are linearly proportional to the dosing. Thiazide diuretics act on distal tubules and block Na and K reabsorption. Initially, they result in reducing plasma volume and reducing vascular resistance by shifting Na to extracellular. They also cause vasodilation. This decrease in plasma volume and Na and K activates RAAS and closing of K channel in the arterial wall due to low K which results in vaso constriction and blunts the effects of thiazide; this makes BP difficult to control. Adding ACEI or ARB not only prevents the body to have this counter regulatory response but also has an additive effects in reducing BP without requiring an increase in the dose of diuretics. Combination Therapy : There are several classes of hypertensive drugs that can be combined into various combinations. Some of these combinations have beneficial effects such as additional reduction in BP and decrease incidences of cardiovascular events and some don't. In the following pages we will look which combinations offers these advantages and which combinations should be avoided. Diuretics and ACEI OR ARB: According to the JNC recommendation, diuretics are the firstline treatment (3). In most cases, it is unlikely to achieve the target goal with diuretics alone (3, 5). Adding ACEI or ARB will counter the body regulatory response because of diuretics, but this combination also has synergestic BP reduction(2,4,11) and reduces the risk of stroke, CAD, MI, stroke and mortality in hypertensive patient(3,4,5). In a study PROGRESS (Perindopril Protection Against Stroke Study) showed reduction of recurrent stroke by 43% when indapamide was added to perindopril (13,19). Studies have shown that it is the reduction of BP that plays an important role in preventing cardiovascular events than individual cardio-protective drugs (2) in hypertensive patients. It also decreases the risk of hypokalemia in patients treated with diuretics alone. It is a good combination in chronic renal insufficiency and diabetic patients (4, 10). This is a preferred combination (13). Diuretics + Beta Blocker : Although this combination has additive BP reduction and Bblockers does attenuate thiazide induced RAAS and decreases heart rate, B-blocker alone or in combination failed to show reduction in cardiovascular events or mortality (2, 4, 12, 13). Sudden cardiac death in elderly patients was higher in B-blocker alone or in combination with diuretics group (12, 20). This combination is a not preferred (4, 12) and reserve in special situation like post MI or angina (4, 5, 12, 14). Side effects like glucose Diuretics + Calcium Channel Blockers This combination has no significant advantage over ACEI/ARB + diuretics (2, 4, and 12). It has no additive effect on blood pressure reduction (4, 12). Studies like VALUE (Valsartan Antihypertensive Long-Term Use Evaluation) showed that amlodipine and hydrochlorthiazide reduced cardiovascular events similar to Valsartan and hydrochlorthiazide group(2, 4), but side effects like electrolyte abnormality, fatigue and tiredness could be an issue. Diuretics do attenuate CCB induced edema (5). Calcium Channel Blocker (Dihydropyridine) + B-Blockers Dihydropyridine like amlodipine causes vasodilation which paradoxically increases heart rate. Adding b-blocker counters these effects and has additive effects in decreasing BP. This combination is a good choice in post-mi and angina patients (2, 4, 5, 12). Combination of non-dihydropyridine and b-blockers should be avoided as it may result in bradycardia or heart block ACEI/ARB and B-blocker : This combination is considered cardio-protective but has no additional reduction in BP (2, 4, and 12). Decreasing the BP to target goal plays an important role in decreasing cardiovascular events than individual or combined cardio-protective therapy. This combination can be used in CAD or heart failure (2, 4, 12). ACEI/ARB AND CCB : This is a preferred combination with respect to cardiovascular end point. It reduces mortality rate associated with MI and stroke by 20% as compared with other combinations especially in patients with other co morbidity (2, 4, 5, 12, 13). Although, results in additional lowering of BP were comparable with ACEI and diuretics, adding ACEI or ARB counters some of the side effects of CCB resulting less side effects. In a study ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension) combintaion therapy benazepril plus amlodipine was superior in reducing cardiovascular events and mortility then benazepril plus hydrochlorthiazide (4,5,15)

3 4416 TABLE 1: Available Combinations: Irbesartan/HCTZ 150mg-12.5mg tablet 300mg-12.5mg tablet Losartan Potassium/HCTZ 100mg-12.5mg tablet 100mg-25mg tablet 50mg-12.5mg tablet Telmisartan/Hydrochlorothiazide 40mg-12.5mg tablet 80mg-12.5mg tablet Valsartan/Hydrochlorthiazide 80mg-12.5mg tablet 160mg-12.5mg tablet 160mg-25mg tablet 320mg-12.5mg tablet 320mg-25mg tablet Synergistic reduction in BP (5,13) Good combination and decrease mortality and complications in diabetics Benazepril/Hydrochlorthiazide 5mg-6.25mg tablet 20mg-12.5mg tablet 20mg-25mg tablet heart failure and stroke (5,13,3,4.10) Enalapril/Hydrochlorthizide 5mg-12.5mg tablet 10mg-25mg tablet Decrease the risk of Hypokelemia (13,5,2) Fasinopril/Hydrochlorthiazide Fasinopril/Hydrochlorthiazide Lisinopril/Hydrochlorthiazide 20mg-12mg tablet 20mg-12.5mg tablet 20mg-25mg tablet Moexipril/Hydrochlorthiazide 7.5mg-12.5mg tablet 15mg-12.5mg tablet 15mg-25mg tablet Quinapril/Hydrochlorthiazide 20mg-12.5mg tablet 20mg-25mg tablet Preferred combination for uncomplicated HTN (Evidence level A,13,10, 15,16)

4 4417 DIURETICS+BETA BLOCKER Atenolol/Chlorthalidone 50mg/25mg tablets 100mg/25mg tablet Bisprolol/Hydrochlorthiazide 2.5/6.25mg tablet 5mg/6.25mg tablet 10mg/6.25mg tablet Metoprolol/Hydrochlortiazide 50mg/25mg tablet 100mg/25mg tablet Nadolol/Hydrochlorthiazide 40mg/25mg tablet 80mg/25mg tablet Propranalol/hydrocholthiazide 40mg/25mg tablet 80mg/25mg tablet Better outcome in African American (2,4) Non prefer combination for un-complicated HTN side effects like sexual dysfunctions, fatigue, glucose intolerance could be an issue DIURETICS/CCB Exforge (Valsartan/amlodipine/HCTZ) Combination of 3 classes Usually reserve for patient who failed other combinations of Two classes CCB+BETA BLOCKERS: None is available in fixed dose Combination. Can be used in patients with Co-morbidities like heart Failure, post MI and angina (2, 4)(Only dihydropyridine)

5 4418 ARB/ACEI+CCB: Amlodipine/Valsartan (Exforge) 5mg/160mg tablet 5mg/320mg tablet 10mg/160mg tablet 10mg/320mg tablet Telmisartan/Amlodipine 40mg/5mg tablet 40mg/10mg tablet 80mg/5mg tablet 80mg/10mg tablet Amlodipine/Benazepril 2.5mg/10mg tablet 5mg/10mg tablet 10mg/20mg tablet 10mg/40mg tablet Prefer combination in uncomplicated HTN (2, 4, 5, 12, 13) Combination Therapy in Managing Hypertension with comorbidities Managing hypertension in a population having co-morbidities is challenging. Hypertensive Patients with co-morbidities have lower set of target value and need to lower BP in an efficient way. In such cases, most of the physicians, experts, and JNC-7 recommendations are to use combination therapy in achieving the target goal (A) (2, 3, 4, 12, 13, 20, 21). Diabetes: Having both Hypertension and diabetes is very common in general population. Presence of hypertension in diabetic patient accelerate the progression of diabetics retinopathy, coronary artery disease, decrease renal functions and other complications (21,22,23). The goal for treatment of hypertension is more stringent in diabetic population. It is a general consensus and also JNC-7 recommendations to start a therapy which includes ACEI/ARB, CCB or diuretics. In various studies, it is showed that combination therapy with ACEI/ARB with CCB or Diuretics has beneficial effects then other available combinations.(2,3,4,5,18,22,23) or monotherapy. Heart failure: Hypertension is an avoidable risk factor for CHF. It requires more aggressive control of BP in Heart failure patients to reduce the mortality. According to JNC guidelines Combination use of diuretics, beta blocker, ACEI/ARB and spironolactone are recommended (3,4,5) depending upon the severity and type of HF. Post-MI: General consensus and JNC guideline recommends use of ACEI/ARB, Beta Blocker plus-minus spiraonolactone.(3,4,5) CAD: Hypertension exacerbates artheroscloretic process by inducing damage to endothelial lining of blood vessels. It may also cause artheroscloretic plaque more unstable and may lead to stroke. Controlling BP is very important in preventing the complication and mortality. Common consensus and JNC guideline is using ACEI/ARB, diuretics, CCB, and B-Blockers. In various studies b-blocker and diuretics verses ACEI/ARB+CCB showed similar efficacy regarding reduction in BP and cardiovascular events (5, 24). However, b-blockers may be less effective in older patients with CAD (24). STROKE: In a study PROGRESS combination therapy with ACEI/ARB+diuretics showed significantly reduction in stroke then monotherapy with ACEI/ARB(5,25).

6 4419 Table 2: Combination therapy for HTN with co-morbidities Co-morbidity Combination Therapy DIABETIES ACEI/ARB+CCB (3, 5, 18, 2, 4)(A) ACEI/ARB+diuretics (3, 5, 2, 4) HEART FAILURE ACEI/ARB+diuretics(3,4,5)(A) ACEI/ARB+b-blocker (3,4,5)(A) mono therapy then selecting prefer combinations over nonprefer combinations for un-complicated or complicated hypertension depending upon individual patients needs, side effects and cost would have better impact on patients compliance and health. ABBREVIATIONS POST-MI ACEI/ARB+b-blocker+aldosterone (3, 4, 5)(A). CAD: ACEI/ARB+diuretics (3, 4, 5)(A) ACEI/ARB+CCB (3, 4, 5) STROKE ACEI/ARB+diuretics(3,4,5,12.13)(A) ACEI/ARB+CCB (2, 4, 5, 12, 13) BP=Blood Pressure, CVS=Cardio Vascular System, RAAS=Renin-Angiotensin-Aldosterone System, CAD=Coronary Artery Disease, ACEI=Angiotensin Converting Enzyme Inhibitor, ARB=Angiotensin Receptor Inhibitor. JNC=Joint National Committee for Prevention, Detection,Evaluation and treatment of High Blood Pressure, CCB=Calcium Channel Blocker ACKNOWLEDGMENTS: The author acknowledged Dr. Romeo Castillo, Program Director Loma Linda Family Practice Rural Program, Hanford, CA and Dr. Jared Garrison, Medical Director Rolling Hill Clinic, Corning, Level of Evidence A=High-quality randomized control trial, high-quality metaanalysis. B= Nonrandomized clinical trial, nonquantitative systemic review C= Consensus, expert opinion D= Anecdotal evidence Adapted from Siwek J,et al. How to write an evidence-based review article. Am Fam Physician 2002; 65:251-8 SUMMARY JNC-7 recommended starting combination therapy when monotherapy failed to achieve the targeted goal or starting combination therapy when systolic and diastolic BP is above 20/10 mm Hg over the goal. European Society of Hypertension & Cardiology suggest to start combination therapy as an initial therapy for complicated and uncomplicated hypertension (5,17). There is some disagreement among authors and clinicians about when to start the combination therapy. Some clinicians prefer to start combination therapy as an initial treatment plan and some opt for a trial of monotherapy first. However, most of them agree that approximately 70% patients with hypertension would require combination therapy, and combination therapy is a preferred treatment if patients have co-morbid conditions. Selecting proper combination is challenging and important for managing hypertension in patients with different ages, ethnicity and comorbidities. There are several guidelines available and it's up to the discretion of a physician to choose how he/she like to manage REFERENCES: 1. Merck Manual, Nineteenth Edition, Combination Therapy in hypertension, A.H. Gradman et al. journal of the American Society of Hypertension 4(1)(2010) The Seventh Report of the Joint National Committee on Prevention, Detection and Evaluation and Treatment of Hypertension. 4. PL Detail-Document, Antihypertensive Combinations. Pharmacist's Letter/Prescriber's Letter April Jannifer Frank, Managing Hypertension Using Combination Therapy, Am Fam Physician, 2008 May 1; 77(9): Dickerson JE, Hingorani AD, et al. Optimisation of antihypertensive treatment by crossover rotation of four major classes, Lancet 1999; 353: Sica. DA. Rational for Fixed Dose Combination in the Treatment of Hypertension: the cycle repeats.drugs2002;62: Weber MA. Julius S. Kjeldsen SE et.al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE trial. Lancet 2004;363; (Ascherio A, Rimm EB, Stampfer MJ, et al. Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease N Engl J Med 1995;332:977-82). 10. Patel A. ADVANCE Collaborative Group. MacMahon S.et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes (the ADVANCE trial) lancet 2007, Bakris GL, Weir MR, Black HR. Improving blood pressure control rates: is there more we can do? J Clin Hypertens (Greenwich), 2007;9(2): Kalra et al. Combination therapy in hypertension: An update Diabetology & Metabolic Syndrome 2010, Combination therapy for hypertension. Pharmacist's letter/ Presciber's letter 2010 (last modified January 2012); 26(10): Beta-blocker for hypertension; help or harm? Pharmacist's letter 2008;24(12) Jamerson K,Weber MA,Bakris GL,et al.benazepril plus amlodipine or hydrochlorthiazide for hypertension in high-risk patients. N.Engl J Med

7 Siwek J.et al.how to write an evidence-based clinical review article. Am Fam Physician 2002;65: Erdine S, Ari O, Zanchetti A, et al. ESH-ESC guidline for management of hypertension.herz.2006;31(4): Tobe S,Kawecka-Jaszcs K, Zannad F. Vetrovec G. Patni R. Shi H. Amlodipine in Diabetes (ANDI) trial. J Clin Hypertens (Greenwich),2007;9(2): Van Gijn.J. The PROGRESS trial: preventing strokes by lowering blood pressure in patients with cerebral ischemia. Emerging therapies; critique of an important advance. Stroke 2002;33; Pepine, Carl J., et al. "A calcium antagonist vs a non calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial." Jama (2003): PROGRESS Collaborative Group. Randomised trial of perindopril based blood-pressure lowering regimen among individuals with previous stroke or transient ischemic attack. Lancet,2001;358(92587): Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122: Messerli FH. Grossman E: Beta-Blockers and Diuretics: To use or Not to Use. Am J Hypertens 1999,12(pt 1-2): Fisman EZ, Tenenbaum A (eds): Cardiovascular Diabetology: Clinical, Metabolic and Inflammatory Facets. Adv Cardiol. Basel, Karger, 2008, vol 45, pp Sowers JR, Levy J, Zemel MB Division of Endocrinology, Wayne State University, School of Medicine, Detroit, Michigan. The Medical Clinics of North America [1988, 72(6): ] 23. Grossman, Ehud, and F. Messerli. "Hypertension and diabetes." (2008): c Copyright 2010 BioMedSciDirect Publications IJBMR -ISSN: 0976:6685. All rights reserved.

Antihypertensive Combinations

This Professional Resource gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER October 2016 ~ Resource #321047 Antihypertensive Combinations