Hypertension (HT) is a well-established risk factor1

High-risk Hypertension and Its Clinical Implications C VENKATA S RAM*, KK AGGARWAL ABSTRACT Hypertension (HT) is a well-established risk factor for cardiovascular disease (CVD) and chronic kidney disease (CKD). Only <50% of treated hypertensive patients have a BP of <140/90 mmhg, which is a cause for much concern. These treated but inadequately controlled hypertensive patients are at significant risk for developing CVD and other complications. Telmisartan is a long-acting angiotensin receptor blocker (ARB), which has multiple positive effects aside from its antihypertensive efficacy. It reduces CV events in high-risk patients, has favorable effects on endothelial function including renoprotective effects. Trials like the MAPHY and BCAP have shown that β blockers (metoprolol) have beneficial effects on outcomes and survival along with reduction in BP. Most hypertensives need combination approach to control their high BP. Being cardioprotective drugs, combination of telmisartan and metoprolol is beneficial for secondary prevention of cardiovascular events in high-risk patients with HT. Keywords: Hypertension, renoprotective, combination, cardioprotective Hypertension (HT) is a well-established risk factor1 for cardiovascular disease (CVD) and chronic kidney disease (CKD). High blood pressure (BP) is associated with development of CVD in a continuous and graded manner; risk increases with incremental BP, even within the normal range. 2 HT is also associated with target organ damage viz. left ventricular hypertrophy (LVH), proteinuria and renal failure, retinopathy and vascular dementia. 3 The Framingham study showed that HT often occurs in association with other atherogenic risk factors. 4 The high prevalence of diabetes and insulin resistance in India may have a major role in the risk for HT. 5 Presence of multiple risk factors greatly increase risk for cardiovascular events. 6 Poorly-controlled BP accounts for 62% cases of cerebrovascular disease, 49% of ischemic heart disease (IHD) and 7.1 million deaths annually. With an aging population and the rising prevalence of obesity, diabetes and CKD, the incidence of resistant HT is only going to rise. 7 The fact that only <50% of treated hypertensive patients have a BP of <140/90 mmhg also is a cause for much *Senior Consultant, Apollo Hospitals Director, Apollo Institute of Blood Pressure Management and Director, Blood Pressure Clinics, Apollo Group of Hospitals, Hyderabad Senior Physician and Cardiologist Moolchand Medcity, New Delhi concern. These treated but inadequately controlled hypertensive patients are at significant risk for developing CVD 8 and other complications. Uncontrolled HT increases risk of atherothrombotic stroke, myocardial infarction (MI), LVH, atrial fibrillation (AF) congestive heart failure, renal failure and hypertensive retinopathy. 9 A 10 mm decrease in systolic BP and a 5 mm decrease in diastolic BP significantly reduced risk of all CVD events including stroke. 10 Risk of clinical events associated with HT is determined by: 11 Absolute and relative BP levels Calculated cardiovascular risk - estimated from factors like age, gender, smoking history, etc. Presence of target organ damage Presence of established CVD or comorbid disease such as diabetes or CKD associated with high CVD risk. References: 1 Benndorf RA, et al. J Hypertension 2008;26(5): 854-6. 2 Sierra C, et al. Vasc Health Risk Manag 2008;4(2):289-96. 3 Nadar SK, et al. Curr Pharm Des 2006;12(13):1581-92. 4 Kannel WB. J Hum Hypertens 2000;14(2):83-90. 5 Ram CV, et al. J Clin Hypertens (Greenwich) 2012;14(8):561-5. 6 Johnson ML, et al. Am J Manag Care 2004;10(12):926-32. 7 Bravo E. Cleve Clin J Med 2013;80(2):91-6. 8 Neutel JM. Nephrol Dial Transplant 2006;21(6):1469-73. 9 Indian guidelines on hypertension (I.G.H.) - III. 2013. J Assoc Physicians India 2013;61(2 Suppl):6-36. 10 Ram CV, et al. J Am Soc Hypertens 2014;8(2):142-3. 11 National Clinical Guideline Centre (UK). Hypertension: The Clinical Management of Primary Hypertension in Adults: Update of Clinical Guidelines 18 and 34 [Internet]. London: Royal College of Physicians (UK); 522 Indian Journal of Clinical Practice, Vol. 25, No. 6, November 2014

2011 Aug. (NICE Clinical Guidelines, No. 127.) 8, Assessing cardiovascular risk, target organ damage and secondary causes of hypertension. Available from: http://www.ncbi.nlm. nih.gov/books/nbk83281/ TELMISARTAN IN HIGH-RISK PATIENTS WITH HYPERTENSION Telmisartan, a long-acting angiotensin receptor blocker (ARB), has therapeutic effects that go beyond BP control. 1 The very high lipophilicity and high volume of distribution give it the clinically important advantage of good tissue penetration. 2 It has multiple positive effects not only on BP, but also on target organ protection. Telmisartan: A Cardiometabolic Sartan 3,4 Antihypertensive efficacy: Greater and more consistent lowering of BP over the full 24-hour period thereby protecting from adverse effects of early morning BP rise on cardiovascular risk. Favorable metabolic profile, especially on insulin sensitivity; neutral effects on sympathetic cardiovascular function and lipids. Cardioprotective effects z Effective in favoring the regression of cardiac and vascular organ damage z Reduces arterial stiffness and improves vascular distensibility z Reverses endothelial dysfunction typical of HT, especially with comorbid diabetes, obesity, renal failure or metabolic syndrome z Reduces central aortic BP. Telmisartan Reduces Cardiovascular Events in High-risk Patients The Telmisartan Randomized AssessmeNt Study in ACE intolerant subjects with cardiovascular Disease (TRANSCEND) study examined the effect of telmisartan on cardiovascular events in high-risk patients who were intolerant to ACE inhibitors. A post-hoc analysis investigated the hypothesis that telmisartan has a differential action in hypertensive vs nonhypertensive patients. 5,6 z The primary composite endpoint (sum of cardiovascular death, nonfatal MI, nonfatal stroke and hospitalization due to heart failure) was nonsignificantly reduced in telmisartan-treated patients vs placebo (15.7% vs. 17%; relative risk reduction 8%). z The occurrence of the secondary endpoint (cardiovascular death, MI and stroke) was significantly lower in telmisartan group (13.0%) vs placebo (15.0%, p < 0.05) only in hypertensive patients. z Post-hoc analysis suggested that MI could be further reduced by telmisartan in hypertensive patients. z Telmisartan could also decrease new onset of LVH in both nonhypertensive and hypertensive patients and new onset of microalbuminuria and macroalbuminuria in hypertensive patients. AF is associated with increased cardiac and vascular risks, mainly stroke. 7 The prevalence of AF in the society is increasing due to aging population. Telmisartan prevented AF recurrences more effective than other antihypertensive drugs among hypertensive patients with paroxysmal AF. 8 In the ONTARGET study in high-risk patients, telmisartan reduced cardiovascular events similar to ramipril, beyond BP-lowering alone, but with a better tolerability. 3 Telmisartan has Favorable Effects on Endothelial Function Endothelial dysfunction is now a recognized marker for cardiovascular risk. 7 A meta-analysis of seven randomized controlled trials of telmisartan for flow-mediated dilatation (FMD) from Japan enrolling a total of 398 patients confirmed the evidence of a significant increase in FMD with telmisartan, suggesting that telmisartan may improve endothelial dysfunction. The pooled analysis of these seven trials revealed a statistically significant increase in FMD by 48.7%, with telmisartan relative to control in the randomeffects model. Removal of any single trial from the assessment had no significant effect on the overall result. No evidence of significant publication bias was evident. 9 In a study, 51 hypertensive patients with coronary artery stenosis but no coronary artery spasm, treated with a sirolimus-eluting stent, were randomly assigned to either telmisartan (n = 25) or amlodipine (n = 26) treatment. Telmisartan significantly improved endothelial dysfunction after coronary drug-eluting stent implantation vs amlodipine in patients with HT in terms of vasoconstriction induced by acetylcholine. 10 Telmisartan: Renoprotective Effect The Atherosclerotic Risk In Communities (ARIC) cohort study and Cardiovascular Health Study have shown Indian Journal of Clinical Practice, Vol. 25, No. 6, November 2014 523

an association between reduced glomerular filtration rate (GFR) and CVD. The lower the GFR, higher the cardiovascular risk. 11 In a multicenter, prospective trial, telmisartan was not only effective and safe in reducing BP in diabetic and nondiabetic, hypertensive, proteinuric CKD patients, even in those who had mildto-moderate chronic renal failure, proteinuria also reduced considerably. 12 Telmisartan administered once-daily was also effective and well-tolerated as treatment of mild/moderate HT in CKD patients, with preservation of renal function. 13 Other clinical trial such as ARAMIS (614 patients with isolated systolic HT and albuminuria, no diabetes), 14 INNOVATION (514 hypertensive or normotensive subjects with type 2 diabetes and microalbuminuria but no renal failure) 15 and AMADEO (patients with type 2 diabetes with overt nephropathy) 16 have demonstrated a beneficial effect of telmisartan on renal function. Telmisartan Significantly Reduces LVH in Hypertensive Patients Telmisartan causes greater LVH regression than hydrochlorothiazide, carvedilol and ramipril despite similar declines in BP. 17-19 The ONTARGET and TRANSCEND studies show that telmisartan provides optimal cardioprotection, with good tolerability profile in high-risk hypertensive patients. In a subanalysis of data from ONTARGET and TRANSCEND studies, new-onset LVH decreased by 37% in TRANSCEND trial. In ONTARGET study, telmisartan was slightly more effective than ramipril in reducing LVH (nonsignificant). 20 This finding is of clinical significance. References: 1 Destro M, et al. Expert Opin Pharmacother 2011;12(17):2719-35. 2 Wienen W, et al. Cardiovasc Drug Rev 2000;18(2):127-54. 3 Asmar R. Eur Cardiol 2012;8(1): 10-6. 4 Grassi G, et al. J Renin Angiotensin Aldosterone Syst 2008;9(2):66-74. 5 Foulquier S, et al. J Hypertens 2014;32(6): 1334-41. 6 de la Sierra A, et al. J Hypertens Suppl 2009;27(2): S22-5. 7 Baguet JP, et al. Integr Blood Press Control 2010;3: 81-9. 8 Pan G, et al. Cardiovasc Ther 2014;32(4):184-8. 9 Takagi H, et al. Hypertens Res 2014 Apr 10. 10 Terashima M, et al. JACC Cardiovasc Interv 2012;5(2):182-90. 11 Dobre D, et al. Eur Heart J 2009;11(Suppl F):F39-F46. 12 Rysavá R, et al. Blood Press Monit 2005;10(4):207-13. 13 Sharma AM, et al. Clin Nephrol 2005;63(4):250-7. 14 Vogt L, et al. J Hypertens 2005;23(11):2055-61. 15 Makino H, et al. Diabetes Care 2007;30(6):1577-8. 16 Bakris G, et al. Kidney Int 2008;74(3):364-9. 17 Galzerano D, et al. J Hum Hypertens 2004;18(1):53-9. 18 Galzerano D, et al. Am J Hypertens 2005;18(12 Pt 1):1563-9. 19 Petrovic I, et al. J Int Med Res 2005;33 Suppl 1:39A-49A. 20 Verdecchia P, et al. Circulation 2009;120(14):1380-9. METOPROLOL IN PATIENTS WITH HIGH-RISK HYPERTENSION β blockers have for long been used in the treatment of cardiovascular conditions. 1 Metoprolol is a cardioselective (β 1 -selective) lipophilic adrenoceptor blocker. It has been suggested that lipophilic β blockers may be a better choice than hydrophilic β blockers with better outcomes vis-à-vis all-cause mortality. 2 In a meta-analysis of β-blocker studies post-mi, greater risk reduction was associated with β 1 selectivity, lipophilicity and absence of intrinsic sympathomimetic activity. Of the three most used β blockers (atenolol, metoprolol and propranolol), metoprolol, with many of these desirable properties, had the most pronounced beneficial effects including on survival. 3 The MAPHY Study The MAPHY study, a major trial, enrolled patients from 11 countries and was conducted in 66 centers. It compared effects of metoprolol in 1,069 patients with pre-treatment diastolic BP of 100-130 mmhg, with those of a thiazide diuretic (hydrochlorothiazide or bendroflumethiazide) in 1,625 patients with moderately severe HT and included many patients with coronary artery disease and heart failure. 4 Total mortality was significantly lower in metoprolol group. At the end of a mean follow-up period of 4.2 years, there were 28 deaths in the metoprolol group and 54 in the diuretic group, respectively; a difference of 48% in total mortality, which was statistically significant, mainly due to a highly significant reduction in coronary heart disease at this point in time. The MAPHY study demonstrated that metoprolol was superior to a thiazide diuretic in reducing total mortality, cardiovascular mortality and sudden cardiac death for similar reduction of BP. The antiatherosclerotic effect of metoprolol provides a pathophysiological rationale for the improved prognosis with β blockers in patients with myocardial ischemia. 5 This finding separates utility of metoprolol vs other β blockers such as atenolol. The BCAP Study β blockers reduce angina symptoms and also have an antiatherosclerotic effect. 5 By influencing pathophysiology of atheroma progression, they may improve prognosis. The BCAP study (β-blocker cholesterol-lowering asymptomatic plaque) compared effects of low-dose metoprolol (25 mg once-daily) and 524 Indian Journal of Clinical Practice, Vol. 25, No. 6, November 2014

fluvastatin (40 mg once-daily) on carotid intima-media thickness (IMT) progression over 3 years in 793 subjects who had carotid plaque but no symptoms of carotid artery disease. 5 Metoprolol significantly reduced rate of plaque progression in the carotid bulb at both 18 and 36 months ( 0.058 mm/year and 0.023 mm/year, respectively). 5 Total mortality and cardiovascular events were significantly lower with metoprolol (8 vs 19; p = 0.031), probably due to the effect on plaque regression. 6 The BCAP study show that a β-blocker can slow progression of carotid IMT in clinically healthy, symptom-free patients with carotid plaque suggesting a favorable effect on early stages of atherosclerosis. β blockers in Hypertension and Cardiovascular Disease β blockers are among the most commonly used drugs in the treatment of HT. As they are also indicated for other conditions like angina, post-mi, arrhythmias, AF, chronic heart failure, and also in patients with hyperadrenergic states such as thyrotoxicosis and even migraine and essential tremor, they are very useful in hypertensives with these comorbidities. 7 Effective in long-term secondary prevention post- MI. 6,8 Reduce preoperative cardiovascular events in high-risk ischemic patients before major vascular surgery. 6 Improve prognosis in patients with coronary artery disease by reducing adverse events in stable patients and high-risk patients. 6 Improve prognosis in patients with all grades of symptomatic heart failure by reducing mortality. 6 β blockers are an important choice in treatment and prevention of CVD despite the controversy attached to atenolol. References: 1 Ram CV. Am J Cardiol 2010;106(12):1819-25. 2 Kohro T, et al. Circulation 2010;74(5):962-9. 3 Soriano JB, et al. Prog Cardiovasc Dis 1997;39(5):445-56. 4 Wikstrand J, et al. Am Heart J 1988;116(1 Pt 2):338-47. 5 Hedblad B, et al. Circulation 2001;103(13):1721-6. 6 Ong HT. BMJ 2007;334:946-9. 7 Larochelle P, et al. Can J Cardiol 2014;30(5 Suppl):S16-22. 8 Freemantle N, et al. BMJ 1999;318(7200):1730-7. NEED FOR COMBINATION THERAPY High BP is not satisfactorily controlled with monotherapy in most patients. 1 Monotherapy is especially not likely to be a successful strategy in those with comorbidities like diabetes mellitus, heart failure. 2 BP control is more rapidly achieved with an initial combination strategy. 3 Early vs delayed combination treatment has the advantage of reducing risk of cardiovascular events in most patients, an effect which occurs mainly via greater BP decline and more rapid achievement of goal BP. 4 In an overwhelming majority of patients with HT, combination therapy is required and mandated for BP to normal levels. Determinants of BP The three major determinants of BP are renal sodium excretion and resultant plasma and total body volume, cardiac performance and vascular tone. These factors control intravascular volume, cardiac output and systemic vascular resistance, the immediate hemodynamic determinants of BP. 3 The major hemodynamic finding associated with high BP is increase in peripheral vascular resistance. 5 The rise in BP is usually multifactorial, so attempting to control it by interfering with only a single pressor mechanism is not easy. Drugs that are directed at any one component usually produce compensatory (counterregulatory) responses that decrease magnitude of response, even if it was accurately directed at the predominant pathophysiologic mechanism. A limited BP reduction is therefore seen with all available anti-ht drugs. 3 Interfering with multiple pressor mechanisms causes greater and more consistent BP decrease and higher responder rates. 6 Rationale of Combination Therapy Initiating treatment with more than one drug targets multiple physiologic pathways. This increases the probability that the predominant contributory mechanisms would be inhibited. Counterregulatory responses would also be reduced. The result is an increase in responder rates as well as increase in the extent of response in these patients. 3 Greater Efficacy Using two complementary anti-ht drugs in combination will always result in greater efficacy than high-dose monotherapy. 7 Combining drugs from complementary classes has 5-fold greater anti- HT efficacy than increasing dose of one drug. Drugs known to reduce long-term incidence of cardiovascular endpoints are highly preferred. 3 All the clinical trials in HT have tested the usefulness of combination therapy, not monotherapy. Indian Journal of Clinical Practice, Vol. 25, No. 6, November 2014 525

Fewer Side Effects Improving the overall tolerability of treatment is a major factor influencing rational drug combinations. 3 Side effects are fewer with complementary drugs used in combination than with high-dose monotherapy. 7 Adherence to Treatment Combination therapy facilitates long-term adherence to treatment by reducing the number of medications as well as the frequency of dosing required. 3 Combination therapy is more commonly indicated in those with comorbid diabetes, CKD and other highrisk patients and in general whenever treatment goal is to attain lower BP targets. In high-risk patients, the goal BP should be achieved more promptly, which favors initial combination therapy and quicker dos adjustment. A combination of two drugs at low doses should be preferred as first-step treatment when initial BP is in the Grade 2 or 3 range or total cardiovascular risk is high or very high. 8 Rational combination therapy begins with the selection of two-drug combinations that exhibit additive BP reduction, excellent tolerability and a demonstrated ability to reduce cardiovascular endpoints in long-term clinical trials. 5 While two-drug combinations are widely used, we should not hesitate to use triple-drug combinations to achieve the BP goals. Practice Recommendations The European Society of Hypertension/European Society of Cardiology (ESH/ESC), the eighth Joint National Committee (JNC 8) and the American and International Societies of Hypertension (ASH/ ISH) have made recommendations for combination therapy. 9-11 When the BP is >20/10 mmhg above goal, then administration of two drugs as first-line therapy should be considered as recommended by the ESH/ ESC, the ASH/ISH and by some members of JNC-8. This approach may help to achieve target BP within a reasonable time period. References: 1 Canbakan B, et al. Kidney Int Suppl 2011 2013;3(4):349-51. 2 Kalra S, et al. Diabetol Metab Syndr 2010;2(1):44. 3 Gradman AH, et al. J Clin Hypertens (Greenwich) 2011;13(3):146-54. 4 Gradman AH, et al. Hypertension 2013;61(2):309-18. 5 Sever PS, et al. Eur Heart J 2011;32(20):2499-506. 6 Gradman AH, et al. Curr Opin Nephrol Hypertens 2012;21(5):486-91. 7 Neutel JM, et al. Nephrol Dial Transplant 2006;21(6):1469-73. 8 Sierra C, et al. Euro Cardiol 2009. 9 Mancia G, et al. J Hypertens 2013;31(7):1281-357. 10 James PA, et al. JAMA 2014;311(5):507-20. 11 Weber MA, et al. J Hypertens 2014;32(1):3-15. TELMISARTAN + METOPROLOL: RATIONALE OF COMBINATION Telmisartan and metoprolol are both cardioprotective drugs. Used together, they are beneficial in hypertensive patients with coronary artery disease or heart failure for secondary prevention of cardiovascular events when the major goal of therapy is improvement of outcome. There are well-conducted outcome trials wit telmisartan as well as metoprolol. Thus, the combination is likely to exert important benefits in patient with HT. Reference: 1 Gradman AH, et al. J Clin Hypertens (Greenwich). 2011;13(3):146-54. 526 Indian Journal of Clinical Practice, Vol. 25, No. 6, November 2014