The impact of first-line treatment on the global burden of hypertension

by R. E. Schmieder
and A. Jumar, Germany

Department of Nephrology and
Hypertension, Friedrich-Alexander-
University Erlangen-Nürnberg (FAU)


Recent data from Europe indicate that only 40% of patients manage to achieve an adequate level of blood pressure (BP) control. The 2013 European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines discussed the question of whether combination therapy should always be preceded by an attempt to use monotherapy or not. This article will review the impact of first-line treatment on the global burden of hypertension in the light of current treatment guidelines. Poor BP control in Europe has led to an urgent call to action and the proposal of measures to improve BP control. In patients with mild BP elevation and low/moderate cardiovascular risk, the 2013 ESH/ESC guidelines recommend treatment initiation with a single antihypertensive agent. However, recent data indicate that initiating therapy with a single-pill combination may have some major advantages compared to monotherapy. Patients receiving initial combination therapy have a lower drop-out rate than patients given any monotherapy. Target BP has been shown to be reached faster when using initial combination therapy compared to add-on therapy. Adapted-dose combinations have been introduced, and these achieve effective BP control with fewer side effects than monotherapy, thereby improving adherence. Fast BP reduction after treatment initiation increases adherence further and improves cardiovascular outcomes. There is still an unmet need to improve BP control in treated and untreated patients with hypertension, and the evaluation of adapted-dose combinations will be a key issue in the future.

High blood pressure (BP) was identified as the number one, dominant risk factor for global disease burden in 2010.1,2 The increase in annual mortality between 1990 and 2010 accounted for more than 2 million deaths.2 Despite the availability of treatment guidelines and a wide range of therapies, BP control is still suboptimal in many countries. Recent data for Europe indicate that only 40% of patients manage to achieve an adequate level of BP control.1 In 2008, there was an urgent call to action from international experts, who identified six key issues that were preventing better BP control: inadequate primary prevention, faulty awareness of risk, lack of treatment simplicity, therapeutic inertia, insufficient patient empowerment, and unsupportive health-care systems.3 Nevertheless, in 2016, BP control is still suboptimal, with only 39% of hypertensive patients achieving a BP target of less than 140/90 mm Hg.1,4,5 This article will review the impact of first-line treatment on the global burden of hypertension in the light of current treatment guidelines.

Current guidelines on first-line treatment in hypertension

European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines currently recommend targeting BP<140/90 mm Hg with drugs, in addition to lifestyle changes, in patients with grade 1 and 2 hypertension with no or 1 to 2 risk factors.6 To be more precise, antihypertensive medication should be started in patients with grade 1 hypertension when elevated BP has been confirmed by several BP measurements or when ambulatory BP is elevated despite the implementation of lifestyle changes for an appropriate length of time. The current guidelines from 2013 reconfirmed that diuretics, β-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or combination therapy. The guidelines emphasized that the major mechanism for the benefits of antihypertensive therapy is the lowering of BP per se, the effects on cause-specific outcomes of the various agents are similar or differ by only a minor degree, and the type of outcome in a given patient is unpredictable. Nevertheless, all classes of antihypertensive agents have their advantages and contraindications.6

The 2007 ESH/ESC guidelines mentioned that, no matter which drug is used, monotherapy can effectively reduce BP in only a limited number of hypertensive patients and that most patients require the combination of at least two drugs to achieve BP control.6 The next set of ESH/ESC guidelines in 2013 discussed the question of whether combination therapy should always be preceded by an attempt to use monotherapy or whether it was preferable to use combination therapy as an initial approach.7 The guidelines emphasized that treatment initiation with monotherapy allows effectiveness and adverse effects to be ascribed to that agent. Disadvantages of this approach were also discussed: finding an alternative, more effective monotherapy when the previous monotherapy is insufficiently effective or ineffective may be a painstaking process and discourage adherence, the pivotal prerequisite to achieving long-lasting BP control.7 The current guidelines mention that patients receiving combination therapy have a lower dropout rate than patients given any monotherapy7 and that a meta-analysis of more than 40 studies has revealed that combining two agents from any two classes of antihypertensive drugs reduces BP much more than increasing the dose of one agent.8 Other advantages of initial combination therapy are: a prompter response in a large number of patients; and a greater probability of achieving target BP in patients with higher BP values. Even though the advantages stated above were discussed in the 2013 ESH/ESC guidelines, the guideline experts ultimately reconfirmed the suggestion given in the 2007 ESH/ESC guidelines,9 in other words initiating treatment with a drug combination only in patients at high risk or with markedly high baseline BP.6 In patients with mild BP elevation and low/moderate cardiovascular risk, the 2013 ESH/ ESC guidelines recommend treatment initiation with a single antihypertensive agent.6 These recommendations are now being challenged by the introduction of single-pill, adapted dose combinations, ie, combinations containing two drugs at dosages lower than those suggested for initial monotherapy.

Adherence and physician inertia

Global epidemiological studies show that poor BP control rates are linked to several factors, including poor adherence to treatment and physician inertia. This in turn has a negative impact on BP control and the global burden of hypertension.

Adherence – a key factor in poor blood pressure control
Low adherence concerns a large number of patients. After six months of treatment, at least one-third of patients will have stopped their initial treatment.8 On a daily basis, around 10% of patients forget to take their medication.8 Therefore, adherence is a key factor in the 2013 ESH/ESC guidelines advice on how to improve BP control.7 It has been shown in 4783 patients in 21 phase 4 trials evaluated by a medicationevent monitoring system that compliance and persistence with antihypertensive therapy typically falls to less than 50% in one year. The fall in persistence is attributed to discontinuation of treatment and fall in adherence to poor execution of the dosing regimen.8 It is known that patients with high persistence show a significantly greater time-to-first-hypertension- related-event compared to patients with low persistence.9 More precisely, better adherence to antihypertensive agents significantly reduces cerebrovascular risk,10 risk for chronic heart failure,11 and risk for coronary artery disease.12,13

A reduced risk of cardiovascular events due to good adherence has also been demonstrated in a large patient sample in Europe.14 A large systematic review and meta-analysis of 44 prospective studies showed that 9% of cardiovascular disease events in Europe could be attributed to poor adherence to vascular medications.15

It has been demonstrated for the major drug classes that the incremental effect on systolic BP lowering of doubling the dose of monotherapy is around 20% of that achieved by adding a drug from another class.16 Data from an analysis of 653 patients from three clinical trials revealed that singlepill combination therapy improves BP normalization ratios.17 Daily intake of more than two pills may lead to adherence below 50%.18 There is evidence that the improvement of adherence with single-pill combinations takes place regardless of concomitant medications.19 2013 ESH/ESC guidelines also favor the use of a combination of two antihypertensive drugs at fixed doses in a single tablet to improve daily adherence.7 A single-pill combination makes use of two pharmacological mechanisms,20 thereby increasing efficacy and sometimes reducing side effects, eg, the combination of perindopril with amlodipine substantially reduces the occurrence of edema.21,22

Active participation of the patient in the prevention and treatment of hypertension is key to increasing adherence, as emphasized by hypertension experts.1 Empowerment requires the patient to accept responsibility for their own health, commit to making lifestyle changes, and adhere to treatment.1 There is a wide range of tools and solutions available to empower patients, such as for example home BP monitoring, easy-to-use decision tools, hypertensive patient associations, and educational programs.7

Physician inertia – the doctor as a risk factor for uncontrolled BP
In a large sample of hypertensive patients (2014 individuals) treated by cardiologists and general practitioners it was demonstrated that more motivated physicians had higher rates of patients with controlled BP.23 This has been attributed to the more confident and optimistic approach to hypertension of these physicians and their more empathetic and supportive patient treatment. Even after adjustment for sociodemographic, clinical, and psychological patient-related variables, separate analyses for the patient groups included in the survey found that the gradient of systolic BP reduction decreased significantly according to physicians’ level of motivation.23 These results underline the importance of physicians’ perception of hypertension, aside from their compliance with international guidelines, for the successful management of hypertensive patients.23

Physician inertia was found to be a major reason for lack of uptitration of treatment and BP control in large randomized controlled trials in hypertension.24 Major examples of these include LIFE (Losartan Intervention For Endpoint reduction in hypertension), VALUE (Valsartan Antihypertensive Long-term Use Evaluation), ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), and ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension).1 In a large retrospective cohort study including 62 US practices and conducted in 7252 hypertensive individuals, antihypertensive therapy was increased in only 13.1% of visits with uncontrolled BP.25 It was estimated that if we could eliminate inertia, systolic BP would be 13.8 mm Hg and diastolic BP 4.5 mm Hg lower.

Possible reasons for physicians’ inertia in hypertension are overestimation of the care provided, the use of “soft” reasons to avoid intensification of therapy, and a lack of education, training, or practice organization aimed at achieving treatment goals. It has been proposed by a European survey of physicians’ attitudes, SHARE (Supporting Hypertension Awareness and Research Europe-wide), that physicians may lack confidence in BP measurements and be hesitant to reduce BP further.5 The SHARE trial revealed that on average physicians were satisfied with a mean systolic BP of 131.6 mm Hg, were concerned by a mean systolic BP of 148.8 mm Hg, and took immediate action when mean systolic BP was 168.2 mm Hg.5 The question remains to what degree do these findings from SHARE accurately reflect the perceptions of physicians in the real world.

The 2013 ESH/ESC guidelines stress the role of team-based strategies in disease management, such as for example the involvement of nurses in implementing lifestyle changes. Team-based care has been shown to reduce systolic BP by around 10 mm Hg and increase BP control by 22%.7,26 One example of the success of team-based care in BP control is a North American professional education program called CHEP (Canadian Hypertension Education Program). CHEP provides annually updated simple recommendations and clinical practice guidelines for the detection, treatment, and control of hypertension. In the first four years after initiation of CHEP, dramatic increases have been observed in the diagnosis and treatment of hypertension.1,27 These improvements in hypertension management have been associated with major benefits in terms of reduction in cardiovascular deaths and hospitalization rates.28

Are we going wrong from the very beginning?
Our intention to catch up

Could therapy initiation with adapted-dose combinations help to improve BP control and therefore reduce the global burden of hypertension?

Interestingly, in contrast to the epidemiologic data on worldwide BP control presented above, several clinical trials show that it is possible to achieve BP control in the majority of patients.29 This has been, for example, demonstrated in VALUE, a study including 15 314 patients that took place in a regular clinical setting, in which patients received either valsartan or amlodipine-based treatment. Systolic BP control (<140 mm Hg) at 30 months increased from 21.9% at baseline to 62.2%, diastolic BP control (<90 mm Hg) from 54.2% to 90.2%, and combined control from 18.9% to 60.5%.30 Similarly, the majority of patients in ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial), INVEST (INternational VErapamil-SR/trandolapril Study), ASCOT, and ACCOMPLISH—patients who received combination therapy with two or more drugs—also had BP that was controlled.30,31

There is mounting evidence that initial treatment with adapted- dose combinations can help to improve BP control. Target BP has been shown to be reached faster when using initial combination therapy compared to add-on therapy.32 Faster BP control in VALUE resulted in better BP control in the first 6 months of therapy and also fewer stroke events.33 It has been shown that fast BP reduction after the start of pill intake increases adherence. There is evidence that achievement of target BP is associated with a significantly smaller risk of cardiovascular events and total mortality.32 It will be very interesting to evaluate the direct comparison of adapted-dose combinations versus monotherapy in future clinical trials, not only with respect to BP control but also to hard end points. Indeed, preliminary data point to a lower incidence of events with adapted-dose-combinations (personal communication).


The continuing need to improve the control of high BP has recently been highlighted in a report from the World Health Organization34 and a fact sheet issued by the World Hypertension League and the International Society of Hypertension. 35 In 2015, a working group of European investigators summarized the main challenges affecting the improvement of BP control today and suggested six key measures: (i) identify a BP treatment target of less than 140/90 mm Hg for the majority of patients; (ii) simplify treatment strategies and encourage pill reduction; (iii) decrease therapeutic inertia; (iv) improve patient empowerment; (v) involve health-care systems; and (vi) reduce the prevailing focus on drug costs.1 In this context, the evaluation of adapted-dose combinations is urgently needed. The improvement of BP control rates in untreated and treated populations will be a key issue in the future. ■

1. Redon J, Mourad JJ, Schmieder RE, Volpe M, Weiss TW. Why in 2016 are patients with hypertension not 100% controlled? A call to action. J Hypertens. 2016; 34:1480-1488.
2. Lim SS, Vos T, Flaxman AD, et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2224-2260.
3. Redon J, Brunner HR, Ferri C, Hilgers KF, Kolloch R, van Montfrans G. Practical solutions to the challenges of uncontrolled hypertension: a white paper. J Hypertens Suppl. 2008;26:S1-S14.
4. Banegas JR, López-García E, Dallongeville J, et al. Achievement of treatment goals for primary prevention of cardiovascular disease in clinical practice across Europe: The EURIKA study. Eur Heart J. 2011;32:2143-2152.
5. Redon J, Erdine S, Böhm M, et al.; SHARE Steering Committee. Physician attitudes to blood pressure control: findings from the Supporting Hypertension Awareness and Research Europe-wide survey. J Hypertens. 2011;29:1633- 1640.
6. Mancia G, De Backer G, Dominiczak A, et al; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 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.
7. Mancia G, Fagard R, Narkiewicz K, et al; Task Force Members. 2013 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). J Hypertens. 2013; 31:1281-1357.
8. Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ. 2008;336:1114-1117.
9. Mathes J, Kostev K, Gabriel A, Pirk O, Schmieder RE. Relation of the first hypertension- associated event with medication, compliance and persistence in naïve hypertensive patients after initiating monotherapy. Int J Clin Pharmacol Ther. 2010;48:173-183.
10. Kettani FZ, Dragomir A, Côté R, et al. Impact of a better adherence to antihypertensive agents on cerebrovascular disease for primary prevention. Stroke. 2009;40:213-220.
11. Perreault S, Dragomir A, White M, Lalonde L, Blais L, Bérard A. Better adherence to antihypertensive agents and risk reduction of chronic heart failure. J Intern Med. 2009;266:207-218.
12. Perreault S, Dragomir A, Roy L, et al. Adherence level of antihypertensive agents in coronary artery disease. Br J Clin Pharmacol. 2010;69:74-84.
13. Corrao G, Parodi A, Nicotra F, et al. Better compliance to antihypertensive medications reduces cardiovascular risk. J Hypertens. 2011;29:610-618.
14. Mazzaglia G, Ambrosioni E, Alacqua M, et al. Adherence to antihypertensive medications and cardiovascular morbidity among newly diagnosed hypertensive patients. Circulation. 2009;120:1598-1605.
15. Chowdhury R, Khan H, Heydon E, et al. Adherence to cardiovascular therapy: A meta-analysis of prevalence and clinical consequences. Eur Heart J. 2013; 34:2940-2948.
16. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11,000 participants from 42 trials. Am J Med. 2009;122:290-300.
17. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixeddose combinations of antihypertensive agents: a meta-analysis. Hypertension. 2010;55:399-407.
18. Mancia G, Omboni S, Grassi G. Combination treatment in hypertension: the VeraTran Study. Am J Hypertens. 1997;10:153S-158S.
19. Gerbino PP, Shoheiber O. Adherence patterns among patients treated with fixed-dose combination versus separate antihypertensive agents. Am J Health Syst Pharm. 2007;64:1279-1283.
20. Yusuf S, Pais P, Afzal R, et al; Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009;373:1341- 1351.
21. Messerli FH. Vasodilatory edema: a common side effect of antihypertensive therapy. Am J Hypertens. 2001;14:978-979.
22. Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther. 2008;30:587-604.
23. Consoli SM, Lemogne C, Levy A, Pouchain D, Laurent S. Physicians’ degree of motivation regarding their perception of hypertension, and blood pressure control. J Hypertens. 2010;28:1330-1339.
24. Kjeldsen SE, Julius S, Dahlöf B, Weber MA. Physician (investigator) inertia in apparent treatment-resistant hypertension—insights from large randomized clinical trials. Lennart Hansson Memorial Lecture. Blood Press. 2015;24:1-6.
25. Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals. Hypertension. 2006;47:345-351.
26. Walsh JM, McDonald KM, Shojania KG, et al. Quality improvement strategies for hypertension management: a systematic review. Med Care. 2006;44:646- 657.
27. McAlister FA, Wilkins K, Joffres M, et al. Changes in the rates of awareness, treatment and control of hypertension in Canada over the past two decades. CMAJ. 2011;183:1007-1013.
28. Campbell NR, Brant R, Johansen H, et al; Canadian Hypertension Education Program Outcomes Research Task Force. Increases in antihypertensive prescriptions and reductions in cardiovascular events in Canada. Hypertension. 2009;53:128-134.
29. Jamerson K, Weber MA, Bakris GL, et al; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. New Engl J Med. 2008;359:2417-2428.
30. Julius S, Kjeldsen SE, Brunner H, et al; VALUE Trial. VALUE trial: Long-term blood pressure trends in 13,449 patients with hypertension and high cardiovascular risk. Am J Hypertens. 2003;16:544-548.
31. Struijker-Boudier HA, Ambrosioni E, Holzgreve H, et al. The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials? Int J Clin Pract. 2007;61:1592-1602.
32. Gradman AH, Parisé H, Lefebvre P, Falvey H, Lafeuille MH, Duh MS. Initial combination therapy reduces the risk of cardiovascular events in hypertensive patients: a matched cohort study. Hypertension. 2013;61:309-318.
33. 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;363:2049-2051.
34. World Health Organization. A global brief on hypertension: Silent killer, global public health crisis. global_brief_hypertension/en/. Published April 2013. Accessed December 13, 2016.
35. World Hypertension League; International Society of Hypertension. High blood pressure: why prevention and control are urgent and important. A 2014 fact sheet from the World Hypertension League and the International Society of Hypertension. Fact_Sheet_logos.pdf. Accessed December 13, 2016.

Keywords: adapted-dose combination; hypertension; first-line treatment; global burden; adherence