Current Perspectives on Combination Therapy

Question: Discuss about the Current Perspectives on Combination Therapy. Answer: Introduction: Goal of antihypertensive therapy should eliminate blood pressure rise without adversely affecting quality of life. Maintenance of normal blood pressure (BP) is central to the homeostasis. BP is controlled by different factors like renal sodium excretion, fluid volume in the body and cardiac performance. Hence, different mechanisms are responsible for rise in blood pressure. Drugs acting on the single target would not be able to act on multiple targets. In such case, there would be requirement of drugs acting on multiple targets. Drugs used for hypertension should control intravascular volume, cardiac output and systemic vascular resistance. Use of combination therapy for hypertension as a first line therapy is more helpful in achieving effective blood pressure control as compared to the single drug treatment1. In case, if two physiologic mechanisms are disrupted, there would be possibility of neutralizing counter regulatory mechanisms. This would result in more reduction in the blood pressure. Hence, diuretic drugs acting on the rennin angiotensisn system should be combined with the angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Diauretics can also be given in combination with -blockers, as it inhibits release of rennin. Dihydropyridine calcium channel blockers (CCBs) used to increase level of circulating catecholamines which leads to the stimulation of renin-angiotensin system. Hence, these CCBs can be combined with ACE inhibitors. ACE inhibitors and beta blockers act on the same target like renin-angiotensin system. Hence, combining these two drugs would not be beneficial2. Effective control of hypertension is required in the hypertensive patients especially in patients with co morbidity like diabetes mellitus. In such patients more aggressive blood pressure control is very much required. It is evident that in most of the patients control of blood pressure using monotherapy is as difficult task. Achieving blood pressure in 140/90 mmHg range in hypertensive patients and 130/80 mmHg range in diabetes is not possible in most of the patients. Effective control of blood pressure is required for the reducing the cardiovascular complications3,4. In a study it was proved that 2 mm Hg reduction in blood pressure can reduce stroke and transient ischemic attacks by 15 % and coronary artery disease by 6 5%. Monotherapy for hypertension is beneficial in most of the patients, however more than 50 % patients require combination therapy for effective control of blood pressure. It is recommended that combination therapy is required in patients with systolic blood pres sure (SBP) 20 mm Hg above goal and/or diastolic blood pressure (DBP) above 10 mm Hg. Many factors are responsible for the occurrence of hypertension. In such scenario, control of blood pressure using single drug acting on one target is unrealistic. Drugs used in the combination therapy can act on different targets and can act as complimentary to each other to control blood pressure. Methodology required for the preparation of combination therapy requires two or more drugs to be combined together. Methodology and Results: In this review studies of only randomized clinical trials are considered. Studies were incorporated with patients comprising of essential hypertension and patients with secondary hypertension were excluded from the study. Studies with patients above 18 years were considered for this review. All the studies considered in this review comprised of one arm with combination of two or more antihypertensive drugs and another arm was antihypertensive monotherapy. Results were considered in terms of efficacy of combination therapy in controlling blood pressure and rapidity of controlling blood pressure. Other outcome measures considered were adherence to the combination therapy, occurrence of morbidities and adverse events. Articles were searched form the databases like Cochrane Central Register of Controlled Trials (Central), MEDLINE, and EMBASE. Data was extracted from the selected articles and this data comprised of study design, population characteristic, components of combination therapy , comparator drugs and outcomes of the clinical trial. Articles with bias towards participants blinding, selection bias, data collection and data analysis were not considered for this review. Studies incorporated in this review were group design, randomized trial, controlled trial and cross over design. Pecherina et al., (2014). conducted a randomized study with parallel groups. In this 124 participants were incorporated with 60 % male and 40 % female. Nebivolol and Amlodipine were given in combination with 2.5/2.5 and 5/5 ratio. 24 hours ambulatory blood pressure monitoring was performed for three months. Along with this heart rate, compliance and quality of life were also evaluated. It was observed that these drug combinations produced effective blood pressure control as compared to the individual drugs8. McLay et al., (2000) conducted double blind, placebo controlled randomized multicentre study. In this study 26 participants were incorporated. Felodipine and Metoprolol each at 50mg were administered to the participants. Mean BP prior to initiation of the study were 172 15/ 102 6 mmHg. In this study, 26 hours ambulatory blood pressure monitoring was performed for 12 weeks. Compliance and adverse events were also monitored in the study. Felodipine and Metoprolol combination effectively reduced blood pressure in these participants9. In Hypertension Optimal Trial (HOT), 33 % patients achieved their target BP using monotherapy and 45 % patients achieved their target BP using combination of two drugs. In Strategies in Treatment of Hypertension (STRATHE) study it was observed that combination of -blocker and ACE inhibitor and CCB exhibited more effect as compared to the administration of the same drugs sequentially. This study was conducted for 9 months and it was observed that 62 % patients in the combination therapy and 49 % in the sequential monotherapy exhibited attainment of target BP. Thiazide-diuretics and -blockers were studied in different studies like STOP, MRC, ALLHAT. These combination drugs are well-known drugs for uncomplicated hypertension. Combination of thiazide-diuretics are ACE-inhibitors are more useful in patients with hypertension with congestive heart failure. This combination therapy is very potent therapy and rapid reduction in the hypertension should be monitored in this therapy. Diuretics and AT (angiotensin) 1-blockers (ARB) would be more useful in hypertension with left ventricular hypertrophy as compared to the -blockers and diuretics combination11. Di uretics and calcium antagonist (dihydropyridines) are helpful in treating isolated systolic hypertension (ISH) patients. -blockers and ACE-inhibitors in combination can be used in hypertensive patients post myocardial infarction and in patients with coronary heart disease chromic heart failure. Calcium antagonists (dihydropyridine-type) and -blockers combination drugs are helpful in patients with coronary artery disease. Calcium antagonists and ACE-inhibitors combination drugs are helpful hypertensive patients with nephropathy, coronary artery disease and atherosclerosis. Efficacy and safety of these combinations were established in the ELSA, PREVENT, SECURE and INSIGHT studies. ACE-inhibitors and AT1-blockers are useful in hypertensive patients with diabetic nephropathy and glomerulonephritis. These drugs in combination reduced proteinuria more as compared to the individual drugs12. Advantages : Combination of drugs can reduce doses of all the drugs in the combination. This would be helpful in reducing adverse effects of drugs in combination. It can improve compliance by administering drugs once a day. Synergistic effect can be achieved using combination therapy. These combination therapies are helpful in achieving normal blood pressure, even in patients with difficulty in controlling blood pressure. Hence, combination therapy can be useful in all the subgroups of hypertension patients. As faster blood pressure can be controlled in patients using combination therapy, patients would be willing to stick to the combination therapy for long term use. Response rate is much higher in combination therapy (75%-95%) as compared to the monotherapy (30%-50%). Convenience of consumption is the most prominent advantage of single pill combination therapy6. Disadvantages : Patients consuming combination therapy reported more dizziness as compared to the patients treated with monotherapy. There is possibility of side effects due to side effects due to drug interactions in combination therapy. Combination therapy may increase cost for the patient7. Discussion: In combination therapy, drugs should be selected based on the efficacy of the combination in reducing blood pressure and treating cardiovascular complications like stroke, myocardial infraction and heart failure. However, more emphasis should be given on reducing blood pressure because reduction in blood pressure is the primary determinant of reducing cardiovascular complications. These combination therapies are proved to be useful in reducing blood pressure in patients with diabetes, renal disease and cardiovascular disease13. Elevation in the blood pressure occurs due to multiple factors. Hence, treating blood pressure with monotherapy, may evoke compensatory response and there would be rise in blood pressure due to other mechanism. In such case, combination of drugs acting on different targets of hypertension would be more beneficial in treating hypertension. Keeping this thing in mind, different combinations are developed for treating hypertension. These combinations include reni n angiotensin aldosterone system (RAAS) inhibitor and diuretic, RAAS inhibitor and CCB, renin inhibitor and ARBS, CCBs and diuretics, b-blockers + diuretics, thiazide diuretics and potassium-sparing diuretics, and CCBs and -blockers. In clinical trials it was observed that patients receiving combination exhibited more effect as compared to the administration of same drugs sequentially. On an average, 75 % of patients require combination therapy for achieving target BP. Selection of combination drug and dose of drugs is very important in developing combination therapy because there may be individual differences for response of combination therapy. In hypertensive patients, insufficient BP control itself is risk factor for diabetes. In combination therapy, more emphasis should be given to drugs which are more effective in long term as compared to the short term effects. This would be helpful in reducing long term cardiovascular effects. Combination drugs should act either on different target or it should block counter regulatory mechanism15. In clinical trials it was observed that dose of drugs in monotherapy are approximately 5 times more as compared to the dose of drugs in combination. Pharmcokinetic properties of drugs in combination should be compatible to each other. In combination therapy, target blood pressure should be reached within 4 6 months of the initia tion of the treatment. It would be helpful in maintaining this BP level for long duration irrespective of the follow-up treatment. In recent times, it is recommended that 2 drugs combination should be used if there is BP more than 160/100 mm Hg in patients with uncomplicated hypertension and 150/90 mm Hg in patients with diabetes and other cardiovascular complications. Monotherapy is first choice for first stage hypertension, however recently recommendation was given for combination therapy in stage 1 hypertensive patients. Adverse effect can be problem in both monotherapy and combination therapy. In monotherapy, adverse effect may be due high doses of drugs as compared to the combination therapy. However, in combination therapy adverse effect can be due to drug interactions. Developments of a combination require knowledge of full pharmacology of both the drugs in the combination. There should be rationale for development of combination therapy. Conclusion: Combination therapy for hypertension is widely accepted. Few patients can be effectively treated for hypertension with the combination therapy only. Combination therapy should be efficacious, with high response rate, work in all the subgroups of hypertensive patients, no metabolic side effects and affordable to patients. These combinations comprises of 2 or 3 drugs in a single pill. Antihypertensive drugs with 2 drugs are well established, however enough clinical evidence is not available for combination of 3 drugs. Selection of the drugs for antihypertensive combination therapy is mainly depends on the hemodynamic and metabolic criteria. Combination drugs should be used in a single pill rather than sequential administration. Advantages of combination therapy indicates that characteristics of combination therapy are similar to the ideal drug. In summary, patients should use combination therapy for achieving target BP. References: Coleman TG, Hall JE. Systemic Hemodynamics and Regional Blood Flow Regulation. In: Izzo JL Jr, Black HR, Sica DA, eds. Hypertension Primer. 4th ed. Philadelphia, PA: Lippincott, Williams and Wilkins; 2008. Kettani FZ, Dragomir A, Cote R, Roy L, Berard A, Blais L, et al. Impact of a better adherence to antihypertensive agents on cerebrovascular disease for primary prevention. Stroke; a journal of cerebral circulation. 2009; 40(1):21320. American Diabetes Association: Standards of medical care in diabetes. Diabetes Care 2010, 33(Suppl 1):11-61. Ong KL, Cheung BM, Man YB, Lau CP, Lam KS: Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2004. Hypertension 2007, 49:69-75. Alan H. Gradman, Jan N. Basile, Barry L. Carter, George L. Bakris. Combination Therapy in Hypertension. Journal Of Clinical Hypertension. 2010;4:4250 Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. ESH/ESC 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). Journal of hypertension. 2013; 31(7):1281357. Scotti L, Baio G, Merlino L, Cesana G, Mancia G, Corrao G. Cost-effectiveness of enhancing adherence to therapy with blood pressure-lowering drugs in the setting of primary cardiovascular prevention. Value in health: the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2013; 16(2):31824. Pecherina TB, Vedernikova AG, Evdokimov DO, Klimenkova AV, Barbarash OL. Postregistration study of comparative assessment efficacy of the use of fixed combination of nebivolol and amlodipine for the treatment of patients with moderate and high degree of arterial hypertension. Kardiologiia. 2014; 54(6):218. McLay JS, MacDonald TM, Hosie J, Elliott HL. The pharmacodynamic and pharmacokinetic profiles of controlled-release formulations of felodipine and metoprolol in free and fixed combinations in elderly hypertensive patients. European journal of clinical pharmacology. 2000; 56(8):[52935 pp.]. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet. 1998;351:17551762. Mallat SG, Tanios BY, Itani HS, Lotfi T, Akl EA. Free versus Fixed Combination Antihypertensive Therapy for Essential Arterial Hypertension: A Systematic Review and Meta-Analysis. PLoS One. 2016 22;11(8):e0161285. doi: 10.1371/journal.pone.0161285. eCollection 2016. Mallat SG, Itani HS, Tanios BY. Current perspectives on combination therapy in the management of hypertension. Integrated blood pressure control. 2013; 6:6978. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014; 311(5):50720. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. Journal of clinical hypertension. 2014; 16(1):1426. Nowak E, Happe A, Bouget J, Paillard F, Vigneau C, Scarabin PY, et al. Safety of Fixed Dose of Antihypertensive Drug Combinations Compared to (Single Pill) Free-Combinations: A Nested Matched Case-Control Analysis. Medicine. 2015; 94(49):e2229. Sherrill B, Halpern M, Khan S, Zhang J, Panjabi S. Single-pill vs free-equivalent combination therapies for hypertension: a meta-analysis of health care costs and adherence. Journal of clinical hypertension . 2011; 13(12):898909.