Correspondence to Paolo Verdecchia, FESC, FACC, Fondazione Umbra Cuore e Ipertensione-Organizzazione Non Lucrativa di Utilità Sociale (ONLUS), Ospedale S. Maria della Misericordia, 06129-Perugia, Italy. Email E-mail Address:

From the Fondazione Umbra Cuore e Ipertensione-ONLUS e Struttura Complessa di Cardiologia (P.V., C.C.), Ospedale S. Maria della Misericordia, Perugia, Italy


Fabio Angeli

Struttura Complessa di Cardiologia e Fisiopatologia Cardiovascolare (F.A.), Ospedale S. Maria della Misericordia, Perugia, Italy


Claudio Cavallini

From the Fondazione Umbra Cuore e Ipertensione-ONLUS e Struttura Complessa di Cardiologia (P.V., C.C.), Ospedale S. Maria della Misericordia, Perugia, Italy


Originally published8 Nov 2018https://doi.org/10.1161/CIRCRESAHA.118.314017Circulation Research. 2018;123:1205–1207

If a man will begin with certainties, he shall end in doubts; but if he will be content to begin with doubts, he shall end in certainties.

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—Francis Bacon, The Advancement of Learning. Holborne. 1605


To what extent should blood pressure (BP) be lowered in hypertensive patients? Should ≥1 BP targets be strictly defined? Or should we tailor the goal to individual patients, considering factors such as age, comorbidities, and balancing efficacy and tolerability of treatment?

The recently released 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines state that BP should be lowered to levels 1

Thus, the take-home message of the 2018 ESC/ESH Guidelines is that a BP target 1

Unfortunately, to quote an aphorism attributed to Voltaire, “the perfect is enemy of the good.” Indeed, a few lines below, the European Guidelines1 complicate the message by adding the recommendation (I A) that systolic BP should be lowered to 2

In plain words, hypertensive patients aged ≥65 years should not have their systolic BP lowered 1

Specifically, the guidelines first recommend of being more aggressive with judicio (ie, taking patient’s tolerability, as assessed during the clinical visit, into account). Subsequently, however, the guidelines introduce a sort of formal own judicio consisting of precise safety boundaries not to be exceeded (120 mm Hg in patients aged 1 Thus, 31 years after the first report by Cruickshank et al,3 the 2018 ESC/ESH Guidelines seem to fully endorse, with the strength of a I A recommendation, the implication of the J-curve hypothesis. Namely, an excessive reduction in BP should be avoided because it may expose patients to added risk instead of benefit.

There are abundant pros and cons reports in the literature on the J-curve hypothesis.3–7 The European Guidelines cite, to support the statement that the risk of harm appears to increase and outweigh the benefits when systolic BP is lowered to 8 of the ONTARGET trial (Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial) and TRANSCEND trial (Telmisartan Randomised Assessment Study in ACE Intolerant Participants With Cardiovascular Disease). The ONTARGET and TRANSCEND trials have been conducted in patients aged ≥55 years without symptomatic heart failure at entry and with a history of chronic coronary artery disease, peripheral artery disease, transient ischemic attack, stroke, or diabetes mellitus complicated by organ damage. Patients were recruited in 40 countries and followed up for a median of 56 months. Notably, about 30% of these patients did not have a positive history of hypertension. In analysis by Böhm et al,8 mean achieved systolic BP values 8 by no means shows that achieved BP values 65 years expose an increased risk.

The discrepancy between the lack of J-curve effect on myocardial infarction and stroke and the effect on mortality raise the possibility of reverse causality as potential contributory to results. Indeed, there is ample evidence that, independent of antihypertensive treatment, low systolic BP values are strongly associated with an excess risk of mortality in the final years of life in patients with heart failure, renal failure, and in the general population with and without frailty.9,10 Thus, nonrandomized epidemiological associations linking low systolic BP with higher mortality should be interpreted cautiously because of the likelihood of reverse causality, especially if the low BP values are recorded a few months or years before death. Correctly, Böhm et al8 concluded that it is not possible to rule out some effect of reverse causality in explaining their results.

Interestingly, the study by Böhm et al8 confirms a previous analysis by our group of the same ONTARGET/TRANSCEND database, restricted to patients with coronary artery disease at entry (ie, an ideal population to test the J-curve hypothesis because an excessive reduction in diastolic BP could theoretically lead to coronary hypoperfusion in the presence of significant stenosis). After adjustment for several potential determinants of reverse causality including cancer and heart failure, which entered the analysis as time-varying covariables, a reduction in BP from baseline by 34/21 mm Hg, corresponding to an achieved BP of only 118/68 mm Hg, was associated with a markedly reduced risk of stroke, without any significant increase in the risk of myocardial infarction (Figure).4

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The strong (I A) recommendation of ESC/ESH Guidelines1 that systolic BP should not be lowered 11 a greater reduction in systolic BP, was associated with a greater risk reduction with no evidence of a J-curve effect. In a network meta-analysis by Bundy et al,12 a mean achieved systolic BP 120 to 124 mm Hg was associated with a significant reduction in the risk of CV disease and all-cause mortality even in the comparison with achieved systolic BP levels 125 to 129 mm Hg (hazard ratios of 0.82 (0.67–0.97) and 0.74 (0.57–0.97), respectively). Bangalore et al,13 in a network meta-analysis including trials designed to compare different BP targets, concluded that systolic BP targets 13

On balance, the evidence accrued to date does not support the 2018 ESC/ESH Guidelines recommendation (I A recommendation) which formally defines safety boundaries that should not be exceeded for the risk of increased harm out-weight the benefits.1

Recently, Messerli et al14 remarked a possible rift between those who write the guidelines and those who treat the patients. By applying this concept to the 2018 ESC/ESH Hypertension Guidelines, how should we manage in the daily practice our patients with BP below the safety boundaries and perfect tolerability of treatment? Adherence to guidelines would imply that we should discourage these patients to continue their drug treatment, totally or in part, to bring BP above the safety BP boundaries. If not, there could be a hypothetical risk for a European physician to be indicted, especially in case of ensuing complications, with the charge of noncompliance with the official ESC/ESH Guidelines for enduring a too low BP.

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To conclude, we think that there is robust evidence from randomized trials and meta-analyses that BP should be lowered to lower levels than thought to date. Having said that, instead of fixing rigid BP targets or safety thresholds, what we should pursue in daily practice is the optimal balance between the magnitude of achieved BP reduction and the tolerability of treatment in each single patient.15 Factors such as age and comorbidities should be carefully considered when assessing this balance.15

In our opinion, the 2018 European Guidelines I A recommendation that systolic BP should not be lowered below predefined safety boundaries (120 mm Hg in patients aged

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.