Prof. Guido Grassi
Main Recommendations are :
The European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) several years ago have prepared and published guideline documents regarding the diagnosis and management of the hypertensive state. These joint efforts have led to the publication of the 2003 and later, the 2007 guidelines (2-3), which have been and still are the most authoritative documents in the field. The 2003 ESH/ESC Task Force guidelines stand as the most quoted scientific paper of the past few decades. Although a four-to-five year period is usually observed between two consecutive editions of clinical guidelines on a given topic, the results of recent clinical trials addressing important topics in the management of the hypertensive disease have prompted the ESH Task Force Committee to prepare an updated document integrating and putting together the trials’ results into new recommendations. The document will serve as basis for the preparation of the third version of the ESH/ESC Guidelines in the next few years.
The last few years have brought foward the results of large scale interventional trials. These include the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), the Prevention Regimen For Effectively avoiding Second Stroke (PRoFESS), the Telmisartan Randomized Assessment Study in ACE-I Intolerant Subjects with Cardiovascular Disease (TRANSCEND), the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Action in Diabetes and Vascular Disease, Preterax and Diamicron-MR Controlled Evaluation (ADVANCE), the Hypertension in the Very Elderly Trial (HYVET) and the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) (4-10). Overall these trials addressed important (and largely debated) issues of major clinical relevance, such as the cardioprotective effects of antihypertensive drug treatment in the very elderly, the outcomes of dual blockade of the renin-angiotensin system (ACE-I plus angiotensin II receptors blockers), the treatment of cardiometabolic conditions associated with hypertension and the blood pressure goals to be safely achieved during treatment. The 2009 document (1) aims at updating information collected in clinical trials, meta-analyses and other studies in 5 major areas, i.e.:
Following the statement that in hypertension assessment of total cardiovascular risk is a key step in the decision process on treatment initiation, the 2009 document (1) make a series of recommendations which can be summarised as follows.
The reappraisal document recommends to start drug treatment in grade 1 hypertensive patients at low or moderate risk when blood pressure is equal or above 140/90 mmHg after lifestyle modifications (1-3). These thresholds are similar in elderly hypertensives, based on the results of the already mentioned HYVET Trial (9). Prompter treatment is recommended in grade 2 and 3 hypertension. In patients with high-normal blood pressure (a condition also known under the term of “pre-hypertension”) drug treatment should be delayed when overall cardiovascular risk is low.
As far as goals of treatment are concerned, the 2009 document recommends that systolic blood pressure should be lowered below 140 mmHg (and diastolic to 90 mmHg) in all hypertensive patients, irrespective of their grade of risk. On the basis of the results of recent clinical studies it appears to be prudent to lower blood pressure to values within the range 130-139 for systolic and 80-85 for diastolic. It thus appears that the concept of lower blood pressure goals to be pursued in diabetics or very high risk patients is no longer recommended because there is no evidence from trials of greater benefit nor can the procedure be regarded of easily achieved in current clinical practice. Finally, the document underlines the fact that the so-called “J-curve phenomenon” (i.e. an increase rather than a reduction in the incidence of coronary events when blood pressure values are below 120-125 for systolic and 70-75 for diastolic) suggest not to lower blood pressure values too much particularly in patients with a history of a previous coronary event.
Large-scale meta-analyses confirm that all major antihypertensive drug classes, i.e. diuretics, ACE-inhibitors, calcium antagonists, angiotensin II receptor antagonists and beta-blockers are all capable of reducing elevated blood pressure values. They may differ in the ability to protect against overall cardiovascular risk or cause-specific cardiovascular events, such as stroke or myocardial infarction. Evidence from clinical trials has been also obtained indicating that some drug classes may be more effective in reducing cardiac, vascular and renal organ damage. This may particularly be the case of angiotensin II receptor blockers and ACE-inhibitors and calcium antagonists as well. The 2009 document thus makes the recommendation that in clinical practice the choice of the antihypertensive drug treatment to be employed in a given patient should be based on the patient’s history, presence of associated risk factors including organ damage. Metabolic profile may be also important, taking into account that some drug classes may have deleterious metabolic effects, particularly of pro-diabetogenic nature (diuretics and beta-blockers). New drugs may be useful in this regard. This may well be the case of compounds directly inhibiting renin, such aliskiren, which is under investigation in large scale clinical trials for its potential ability to exert protective effects on organ damage superior to the ones already obtained with other drugs acting on the renin-angiotensin system.
Clinical trials and current clinical practice wok together to show that effective blood pressure control can only be achieved with combination drug treatment. The 2009 document recommends this treatment strategy, which may offer advantages over monotherapy and at treatment initiation, particularly in high risk patients in which an early blood pressure control is indicated. Fixed drug combinations are recommended, with the possibility of choosing between a wide range of two drug combinations, which include an ACE-inhibitor or an angiotensin II receptor blocker with a diuretic or a beta blocker or a calcium channel blocker. The ACE-inhibitor/calcium channel blocker, as shown by the results of the ACCOMPLISH trial (10), may be particularly effective and well tolerated. Given the potential dysmetabolic effects of the diuretic/beta blocker combination, this therapeutic strategy should be avoided, while single components of the associations can be safely combined to other drug classes (particularly those acting on the renin-angiotensin system). The same conclusion should apply to the combination of an ACE-inhibitor and an angiotensin II receptor blocker, in the light of the negative data collected in the ONTARGET trial, particularly for its unfavourable effects on renal function (4).
Given the evidence that in clinical practice hypertension is frequently associated with other dysmetabolic or cardiovascular risk factors or clinical conditions, the 2009 document underlines the clinical benefits of combining a statin or an antiplatelet agent (aspirin) with antihypertensive drugs in the aim of lowering the global cardiovascular risk profile (1). Similar emphasis is given to achieve in diabetic hypertensives, along with a satisfactory blood pressure reduction, a tight glucose control. This should allow to avoid the appearance, or to slow down the progression, of microvascular complications, which in diabetes predispose to cardiovascular events. Lastly the document discusses the potential advantages of the polypill (i.e. a pill containing three antihypertensive agents - an ACE-inhibitor, a beta-blocker and a diuretic - together with a statin and aspirin at low dose) (11). Although promising, the polypill approach requires further evaluation, particularly in the primary prevention of cardiovascular disease.
The 2009 ESH document offers clarifications on a number of clinical questions of great importance in current clinical practice. It also points to the need for new trials, aimed at investigating in particular the benefits of drug treatment in grade 1 hypertension or even in pre-hypertension. These and other therapeutic issues, particularly in diabetics or elderly hypertensives, may be worthy of investigation in future clinical trials.
1. Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, Cifkova R, Clément D, Coca A, Dominiczak A, Erdine S, Fagard R, Farsang C, Grassi G, Haller H, Heagerty A, Kjeldsen SE, Kiowski W, Mallion JM, Manolis A, Narkiewicz K, Nilsson P, Olsen MH, Rahn KH, Redon J, Rodicio J, Ruilope L, Schmieder RE, Struijker-Boudier HA, van Zwieten PA, Viigimaa M, Zanchetti A. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens. 2009;27-2121-2158 2. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. European Society of Hypertension-European Society of Cardiology Guidelines Committee. J Hypertens. 2003;21:1011-1053. 3. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Boudier HA, Zanchetti A. 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
4. ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559. 5. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voigt T, Weber M, Yoon BW. PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 2008;359:1225-1237. 6. Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008;372:1174-1183. 7. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572. 8. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545–2559. 9. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ; HYVET Study Group. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358:1887-1898. 10. Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417-2428.
Guido Grassi Past-Chairman ESC Working Group Hypertension and the Heart Clinica Medica, University of Milano-Bicocca, Milan, Italy.
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