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Dr. Athanasios. J. Manolis,
Dr. Leonidas. E. Poulimenos,
Dr. Manolis. S. Kallistratos,
Despite the indisputable benefits of blood pressure control, worldwide rates in hypertensive patients are discouraging. Data from the National Health and Nutrition Examination Study (NHANES) 2007-2010 indicated that, in approximately 50% of hypertensive patients, BP levels were not controlled. Factors contributing to this phenomenon are mainly clinical inertia and low adherence to treatment. Approximately 40% of patients will discontinue treatment within two years of therapy initiation, and this percentage increases up to 61% within 10 years. In this article we will analyze the benefits of BP treatment, as well as the main causes contributing to clinical inertia and low adherence to treatment, proposing potential solutions to overcome these obstacles.
Nowadays, arterial hypertension (HTN) is considered a major global public health problem. In the general population, its prevalence is estimated to be approximately 20% to 45%, while its incidence increases markedly with population aging (1). In the year 2000, the number of adults with HTN was estimated to be approximately 972 million and this is expected to increase by about 60% by the year 2025 reaching a number of 1.56 billion (2). The continuous relationship of blood pressure (BP) with cardiovascular (CV) and renal events classifies HTN as one of the major risk factors for CV disease morbidity and mortality. Thus, early detection and treatment of arterial hypertension are crucial in order to improve prognosis, a target that is achievable by the diversity of available therapies. In this article, we are going to summarize the benefits and also the limitations of antihypertensive treatment.
There is overwhelming evidence that treatment of HTN and control of BP significantly decrease CV and cerebrovascular events, as well as CV morbidity and mortality, in both men and women (1,3,4). Reductions as small as 2 mmHg in systolic blood pressure reduce the risk of CV events by up to 10% (5), while antihypertensive treatment in general has been associated with a significant reduction of 35-40% in the incidence of stroke, a 20-25% reduction in the incidence of myocardial infarction and a more than 50% reduction in the incidence of heart failure (6). In addition, there is evidence that antihypertensive treatment induces regression of target organ damage since various studies and meta-analyses have shown treatment-related significant reductions in left ventricular hypertrophy, urinary protein excretion, carotid intima media thickness and pulse wave velocity levels (1). It also seems that several drug classes exert pleiotropic effects extending beyond BP control, such as improvement of endothelial function, increase of bradykinin levels, decrease in sympathetic activity showing in general significant antioxidant, anti-inflammatory, antithrombotic, antiatherosclerotic and antifibrotic effects (7-10).
Nevertheless, the fact that some drug classes present additional pleiotropic effects extending beyond BP control does not mean that drugs can be assigned a higher or lower level of priority in the management of arterial hypertension since, according to current ESH/ESC guidelines, the main benefits of antihypertensive treatment are due to lowering of BP per se and are largely independent of the specific drugs employed (1). The choice of an antihypertensive drug should be based on the comorbidities and/or compelling and possible contraindications. The additional pleiotropic effects can be assessed after BP has been controlled.
Apart from the benefits in terms of CV morbidity and mortality, the economic benefits of BP decrease and control with antihypertensive dugs have to be considered, since it is estimated that costs associated with complications of HTN (CAD, stroke, HF, other CV diseases) will increase from approximately $131 billion in 2010 to $389 billion in 2030 in the USA alone (11).
Despite the clear benefits of BP control and the efficiency of available therapies, the rates of hypertensives achieving BP targets are discouraging worldwide. Data from the NHANES 2007-2010 indicated that, in approximately 50% of hypertensive patients, BP levels were not controlled (12). Although several factors are responsible for this phenomenon, clinical inertia and low adherence to treatment probably represent the main reasons. Moreover, excessive reduction of blood pressure seems to be deleterious, especially in elderly patients and in patients with coronary heart disease (J curve phenomenon).
Physician inertia is defined as lack of therapeutic action when BP levels are above the target threshold (1). This phenomenon is more pronounced than expected. In a retrospective study which enrolled 7,253 hypertensive patients, antihypertensive therapy was intensified in only the 13.1% of visits when BP was ≥140/90 mmHg (13). In another study, which assessed the care of 800 hypertensive men over a period of two years of follow-up (average of number of clinic visits >6, 6,391 hypertension-related visits in total), 40% of those patients had BP levels >160/90 mmHg and drug therapy was intensified in only 6.7% of these visits (14). Likewise, several other studies confirm this phenomenon (15-17). Unfortunately, lack of guideline knowledge can explain only a part of this phenomenon. The vast majority of physician inertia is mainly attributed to fear of tissue/organ hypoperfusion (J curve phenomenon, see below), concerns about side effects (1), unrealistic perception of recommendations when physicians try to apply them in their environment (18), underestimation of the risks caused by increased BP levels (especially in the elderly) (1), or due to the fear of poor tolerance and physicians’ reservations in case of existing comorbidities.
Poor adherence to treatment represents a major barrier to BP reduction and control. It is estimated that approximately 40% of patients will discontinue treatment within two years of its initiation. This percentage increases up to 61% within 10 years (19), while on a daily basis approximately 10% of patients forget to take their drug(s) (20). The main reasons for poor adherence to treatment are the presence of side effects, poor tolerability, the complexity and the number of drugs administered, as well as the use of ineffective or insufficiently effective drugs (in terms of BP reduction) which can discourage patients with many treatment changes (1,21,22). A non-adherent patient can be either a discontinuer or a non-regular user (1). As expected, lack of or low adherence to treatment unfortunately increases CV morbidity and mortality. In a registry that enrolled 18,806 hypertensive patients, low adherence to treatment was related to a 38% increase in CV events (23). Similarly, in a cohort that included 242,594 patients with recently initiated hypertension treatment, the same phenomenon was associated with 23% and 24% increases in cerebrovascular and coronary events, respectively (24).
Although there is a continuous relationship of BP with CV events and lowering BP is certainly beneficial, decreasing BP below a critical point is no longer advantageous, but could be deleterious (1): this is mainly attributed to hypoperfusion of vital organs (25). Actually, the J curve describes the relationship between BP reduction and the risk of CV events, while the J shape reflects the increased risk at high and very low levels of BP. Despite the fact that the J curve theory is mainly based on post hoc and meta-analyses (only a few prospective studies have addressed this issue (26)), it seems to be valid in elderly patients and in patients with coronary or peripheral artery disease (1,27). Since a large percentage of hypertensive patients also suffer from theses conditions/comorbidities, treating physicians must be alert in order to avoid an excessive BP reduction that can eventually harm those patients.
In order to decrease physician inertia and improve patients’ adherence to treatment, several approaches have been proposed. Educational and training programs seem to improve physician inertia although not as much as expected (28-30). On the other hand, improving patients’ understanding regarding the goals of BP and the benefits of BP control could improve physician inertia, enhancing patient and physician interaction and collaboration (31). Current ESH/ESC guidelines (1) encourage the distribution of informative material to both patients and health-related providers in order to inform and to improve motivation and clinical inertia, as well as adherence to treatment. Involving the patient in the assessment and treatment of BP (self-monitoring of blood pressure, self-management with a simple patient-guided system) could further improve BP assessment and control (1).
No or low adherence to treatment is mainly caused by the complexity, poor tolerability/adverse events, and the effectiveness of the drug regimen used. Simplifying the drug regimen administered, reducing the number of pills by using fixed combinations, could further improve adherence (1). In a retrospective study which enrolled more than 80,000 hypertensive patients (32), adherence to treatment increased with the decrease in the number of pills prescribed. The use of fixed combinations significantly improves adherence to treatment (by 29%), reducing the risk of non-compliance by 24% relative to the free drug combinations (33). In addition, fixed combination enhances the BP-lowering effect with respect to free drug combinations, decreasing the incidence of adverse events while also lowering the costs of the therapy (34-36).
Assessment and therapy of arterial hypertension are challenging, and the results of blood pressure control have unfortunately been discouraging up until now. Significant efforts from patients and healthcare providers must be made to improve awareness, treatment and control of blood pressure in order to reduce morbidity and mortality rates in these patients.
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7. Vasodilator β-blockers: a different class of antihypertensive agents? Kallistratos MS, Poulimenos LE, Manolis AJ. Future Cardiol. 2014 Nov;10(6):669-71.
8. Not all angiotensin-converting enzyme inhibitors are equal: focus on ramipril and perindopril. Di Nicolantonio JJ, Lavie CJ, O’Keefe JH. Postgrad Med. 2013;125(4):154-168.
9. Cardioprotective properties of bradykinin: role of the B(2) receptor. Manolis AJ, Marketou ME, Gavras I, Gavras H. Hypertens Res. 2010 ;33(8):772-7.
10. Sympathetic overactivity in hypertension and cardiovascular disease. Manolis AJ, Poulimenos LE, Kallistratos MS, Gavras I, Gavras H. Curr Vasc Pharmacol. 2014 Jan;12(1):4-15.
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13. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals. Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Hypertension. 2006 Mar;47(3):345-51.
14. Barriers to hypertension control. Borzecki AM, Oliveria SA, Berlowitz DR. Am Heart J. 2005 May;149(5):785-94.
15. Hypertension management: the care gap between clinical guidelines and clinical practice. Andrade SE, Gurwitz JH, Field TS, Kelleher M, Majumdar SR, Reed G, Black R. Am J Manag Care. 2004 Jul;10(7 Pt 2):481-6.
16. Awareness, knowledge, and attitudes of older americans about high blood pressure: implications for health care policy, education, and research. Egan BM, Lackland DT, Cutler NE. Arch Intern Med. 2003 Mar 24;163(6):681-7.
17. Barriers and facilitators of medication adherence in hypertensive African Americans: a qualitative study. Ogedegbe G, Harrison M, Robbins L, Mancuso CA, Allegrante JP. Ethn Dis. 2004 Winter;14(1):3-12.
18. Patient and general practitioner attitudes to taking medication to prevent cardiovascular disease after receiving detailed information on risks and benefits of treatment: a qualitative study. Gale NK, Greenfield S, Gill P, Gutridge K, Marshall T. BMC Fam Pract. 2011 Jun 26;12:59.
19. Rate and determinants of 10-year persistence with antihypertensive drugs. Van Wijk BL, Klungel OH, Heerdink ER, de Boer A. J Hypertens. 2005 Nov;23(11):2101-7.
20. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. BMJ. 2008 May 17;336(7653):1114-17.
21. Antihypertensive medication adherence, ambulatory visits, and risk of stroke and death. Bailey JE, Wan JY, Tang J, Ghani MA, Cushman WC. J Gen Intern Med. 2010 Jun;25(6):495-503.
22. Barriers to antihypertensive medication adherence among adults--United States, 2005. Vawter L, Tong X, Gemilyan M, Yoon PW. J Clin Hypertens (Greenwich). 2008 Dec;10(12):922-9.
23. Adherence to antihypertensive medications and cardiovascular morbidity among newly diagnosed hypertensive patients. Mazzaglia G, Ambrosioni E, Alacqua M, Filippi A, Sessa E, Immordino V, Borghi C, Brignoli O, Caputi AP, Cricelli C, Mantovani LG. Circulation. 2009 Oct 20;120(16):1598-605.
24. Better compliance to antihypertensive medications reduces cardiovascular risk. Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, Mancia G. J Hypertens. 2011 Mar;29(3):610-8.
25. The J-curve in arterial hypertension: fact or fallacy? Tsika EP, Poulimenos LE, Boudoulas KD, Manolis AJ. Cardiology. 2014;129(2):126-35.
26. Prognostic significance of blood pressure response to exercise in patients with systolic heart failure. Kallistratos MS, Poulimenos LE, Pavlidis AN, Dritsas A, Laoutaris ID, Manolis AJ, Cokkinos DV. Heart Vessels. 2012 Jan;27(1):46-52.
27. Outcomes Among hypertensive patients with concomitant peripheral and coronary artery disease: findings from the INternational VErapamil-SR/Trandolapril STudy. Bavry AA, Anderson RD, Gong Y, Denardo SJ, Cooper-Dehoff RM, Handberg EM, Pepine CJ. Hypertension. 2010 Jan;55(1):48-53.
28. Factors associated with therapeutic inertia in hypertension: validation of a predictive model. Redón J, Coca A, Lázaro P, Aguilar MD, Cabañas M, Gil N, Sánchez-Zamorano MA, Aranda P. J Hypertens. 2010 Aug;28:1770-7.
29. Improvement of hypertension management by structured physician education and feedback system: cluster randomized trial. Luders S, Schrader J, Schmieder RE, Smolka W, Wegscheider K, Bestehorn K. Eur J Cardiovasc Prev Rehabil. 2010 Jun;17(3):271-9.
30. Effectiveness of an Interventional Program to Improve Blood Pressure Control in Hypertensive Patients at High Risk for Developing Heart Failure: HEROIC study. De Rivas B, Barrios V, Redón J, Calderón A. J Clin Hypertens (Greenwich). 2010 May;12(5):335-44.
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33. Evaluation of compliance and health care utilization in patients treated with single pill vs. free combination antihypertensives. Yang W, Chang J, Kahler KH, Fellers T, Orloff J, Wu EQ, Bensimon AG. Curr Med Res Opin. 2010 Sep;26(9):2065-76.
34. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Gupta AK, Arshad S, Poulter NR. Hypertension. 2010 Feb;55(2):399-407.
35. Combination therapy in hypertension. Gradman AH, Basile JN, Carter BL, Bakris GL; American Society of Hypertension Writing Group. J Clin Hypertens (Greenwich). 2011 Mar;13(3):146-54.
36. Blood pressure reduction, persistence and costs in the evaluation of antihypertensive drug treatment--a review. Bramlage P1, Hasford J. Cardiovasc Diabetol. 2009 Mar 27;8:18.
Manolis. S. Kallistratos, MD, PhD, FESC, EHS
Leonidas. E. Poulimenos, MD, FESC
Athanasios. J. Manolis, MD, FESC, EHS, FACC
Cardiology Department, Asklepieion General Hospital, Athens, Greece
Conflict of interest: None declared
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