Effects of lowering diastolic blood pressure to <80 mmhg on cardiovascular mortality and events in patients with coronary artery disease: a systematic review and meta-analysis

ABSTRACT The target of diastolic blood pressure (DBP) remains controversial in patients with coronary artery disease (CAD). We systematically searched PubMed/Medline and the Cochrane Central

database for randomized controlled trials (RCTs) assessing the efficacy and safety of reducing DBP in CAD patients from January 1965 to July 2017. Seven placebo-controlled RCTs enrolling

34,814 CAD patients who achieved DBP <80 mmHg were included in the drug-intervention group. The average achieved blood pressures (BPs) were 126.3/75.1 and 131.5/77.8 mmHg in the

drug-intervention and placebo-control groups, respectively. Drug intervention was associated with an 11% reduction in coronary revascularization and a 31% reduction in heart failure. In the

drug-intervention group, all-cause death, myocardial infarction, angina pectoris, and stroke were reduced with marginal significance, whereas hypotension was increased by 123%. A

meta-analysis of four RCTs, in which the achieved DBP was <75 mmHg, showed that the drug intervention was associated with a 22% reduction in heart failure. These results suggest that

reducing DBP to 80 mmHg or less would significantly reduce coronary revascularization and heart failure but at the expense of causing hypotension in CAD patients. Further trials are

warranted to prove this issue. You have full access to this article via your institution. Download PDF SIMILAR CONTENT BEING VIEWED BY OTHERS INTENSIVE BLOOD PRESSURE-LOWERING TREATMENT TO

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A SYSTEMATIC REVIEW AND META-ANALYSIS Article 13 February 2025 INTRODUCTION It has been well established that reducing blood pressure (BP) can prevent cardiovascular events and death. A

meta-analysis of 61 prospective observational studies showed that BP was strongly and log-linearly associated with cardiovascular mortality down to 115/75 mmHg [1]. In Japanese people, BP is

related to the cumulative incidence of myocardial infarction down to 120/70 mmHg [2]. Importantly, BP reduction is associated with a reduced risk of cardiovascular events irrespective of

the class of antihypertensive drugs used, including angiotensin converting enzyme (ACE) inhibitors, calcium-channel blockers, diuretics, and β-blockers [3]. Thus, it is suggested that BP

lowering per se is important for preventing cardiovascular events. Current Japanese guidelines for hypertension management (JSH2014) recommend a BP target of <140/90 mmHg in patients with

coronary artery disease (CAD) and <130/80 mmHg in high-risk CAD patients if tolerable [4]. However, previous American and European hypertension guidelines have recommended a target of 

<140/90 mmHg for patients with CAD [5, 6] because of a J-curve phenomenon; namely, a nonlinear relationship exists between BP and adverse outcomes with higher event rates at both very-low

and very-high BP [7, 8]. An observational study enrolling CAD patients showed that a systolic BP (SBP) of less than 120 mmHg and a diastolic BP (DBP) of less than 70 mmHg were associated

with an increased risk of cardiovascular disease [9]. An additional analysis of the Systolic Blood Pressure Intervention Trial demonstrated the presence of a J curve for DBP with a nadir of

approximately 70 mmHg based on the automated office BP measurement in hypertensive patients with or without cardiovascular disease; however, there was no J curve for SBP [10]. The most

recent 2017 ACC/AHA guidelines have lowered the BP target for CAD patients from 140/90 to 130/80 mmHg [11]. The following two studies may have an impact on the lowering of the SBP target:

first, the Systolic Blood Pressure Intervention Trial using the automated office BP measurement showed that intensive SBP reduction targeting 120 mmHg significantly reduced not only the

composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, and death from cardiovascular causes but also all-cause mortality, when compared with the standard

SBP reduction targeting 140 mmHg in patients with clinical/subclinical cardiovascular diseases other than stroke and in patients at a high risk for cardiovascular disease but without

diabetes [12]. Second, a large-scale meta-analysis enrolling 66,504 CAD patients demonstrated that an SBP reduction achieving SBP ≤ 130 mmHg was associated with greater reductions in heart

failure and stroke without the increase in all-cause death and cardiovascular death, when compared with the standard SBP reduction of SBP 136–140 mmHg [13]. However, only a few consistent

data are available regarding DBP targets based on randomized clinical trials (RCTs) in patients with CAD. Accordingly, we conducted searches of previous trials and performed a systematic

review and meta-analysis assessing the efficacy and safety of reducing DBP to <80 mmHg in CAD patients. METHODS ELIGIBILITY CRITERIA This systematic review and meta-analysis was conducted

according to the PRISMA statement [14]. We conducted a systematic search of MEDLINE and the Cochrane Central Register of Controlled Trials (CENTRAL) from 1965 to July 2017 using medical

subject headings and relevant text words for CAD and those for BP or DBP. The search criteria were fairly broad to avoid missing studies through a restricted search. We also checked the

reference lists of the original studies, meta-analyses, and review articles that were identified by the electronic searches to find other eligible trials. There was no language restriction

placed on the search. This analysis included RCTs conducted among patients with CAD (excluding the acute phase of myocardial infarction or heart failure) that [1] randomized patients to

antihypertensive drug or placebo arms; [2] reported long-term survival or cardiovascular outcomes for at least 1 year; [3] enrolled at least 500 patients to avoid bias associated with small

trials; [4] attained a DBP of <80 mmHg in the drug-intervention group. Studies reporting no significant difference in DBP between the two groups were excluded. DATA EXTRACTION, SYNTHESIS,

AND ANALYSIS Long-term efficacy and safety outcomes were evaluated. The efficacy outcomes were the following: all-cause mortality, cardiovascular mortality, myocardial infarction, angina

pectoris, revascularization, stroke, and heart failure. The safety outcome evaluated was hypotension, as reported, and compared between the two groups. For data synthesis and analysis, we

used the Cochrane Review Manager software, Review Manager version 5.3 (RevMan 5.3) (Nordic Cochrane Center, Copenhagen, Denmark). ASSESSMENT OF RISK OF BIAS IN THE INCLUDED STUDIES Two

review authors (RO and EK) independently assessed trial eligibility and trial-bias risk and extracted data. Disagreements were resolved by consensus. The bias risk of the trials was assessed

using the six domains of the ‘Risk of bias’ tool according to the method described in the Cochrane Handbook ‘Assessing Risk of Bias in Included Studies’

(http://methods.cochrane.org/bias/assessing-risk-bias-included-studies. Accessed July 11, 2017). STATISTICAL ANALYSIS Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated for

each trial and each outcome. Random-effects models were used to pool RRs and 95% CI for study outcomes. We used the Cochrane chi-squared test and _I_2 statistics to test the heterogeneity

across the trials [15]. A chi-square value of less than 0.05 or an _I_2 value greater than 50% was regarded as indicating high heterogeneity. Publication bias was assessed using funnel

plots. Statistical analysis was performed using RevMan 5.3. ROLE OF FUNDING SOURCE This study was not funded; hence, no funding source played any role in study design; collection, analysis,

and interpretation of the data; or writing the paper. RESULTS TRIAL SELECTION AND STUDY CHARACTERISTICS We identified seven RCTs that fulfilled the inclusion criteria (Fig. 1)

[16,17,18,19,20,21,22]. The characteristics of included trials are summarized in Table 1. The drug-intervention group and the placebo-control group included 17,434 and 16,725 patients,

respectively. Achieved BPs were 126.3/75.1and 131.5/77.8 mmHg in the drug-intervention and placebo-control groups, respectively. Of note, none of the trials were designed to assign patients

to different target levels of SBP or DBP (e.g., DBP less than 80 mmHg). A summary of the risk of bias assessment of each trial is shown in Fig. 4. All seven RCTs were considered to have a

low risk of bias. EFFICACY OUTCOMES The drug-intervention group with an achieved DBP < 80 mmHg tended to have lower all-cause death (RR 0.94, 95% CI 0.86–1.02, _P_ = 0.12; Fig. 2a),

myocardial infarction (RR 0.87, 95% CI 0.74–1.03, _P_ = 0.10; Fig. 2c), angina pectoris (RR 0.88, 95% CI 0.76–1.02, _P_ = 0.08; Fig. 2d), and stroke (RR 0.87, 95% CI 0.73–1.06, _P_ = 0.16;

Fig. 2f) when compared with the placebo group, although the differences were not significant. No significant effect was found when comparing cardiovascular death in the drug-intervention

group with that in the placebo group (Fig. 2b). However, the intervention group was associated with a significant (11%) reduction in coronary revascularization (Fig. 2e) and a 31% reduction

in heart failure (Fig. 2g). There was a low level of heterogeneity for the effects of the intervention across eligible trials for all-cause death, cardiovascular death, stroke, and heart

failure; a modest level of heterogeneity for angina pectoris; and a high level of heterogeneity for myocardial infarction (_I_2 = 56%; Fig. 2c) and revascularization (_I_2 = 66%; Fig. 2e).

There was no clear evidence of publication bias (Supplementary Figure 1). Next, we performed an additional meta-analysis of four RCTs, CAMELOT-E [17], IMAGINE [19], PART-2 [20], and PEACE

[21], in which a DBP of <75 mmHg was attained in the drug-intervention group. When the achieved DBP was <75 mmHg, the drug intervention was associated with a 22% reduction in heart

failure when compared with the placebo group (Fig. 3g). There was no heterogeneity for the outcome of heart failure (_I_2 = 0%; Fig. 3g). In the drug-intervention group, a trend towards

reduced all-cause death was observed (Fig. 3a), but there were no significant reductions in cardiovascular death, myocardial infarction, angina pectoris, revascularization, and stroke (Fig. 

3b–f). There was no clear evidence of publication bias (Supplementary Figure 2). SAFETY OUTCOME The drug-intervention group with an achieved DBP of 80 mmHg or less was associated with a 123%

increase in hypotension rate (Fig. 2h) when compared with the placebo-control group. There was high heterogeneity in the analysis (_I_2 = 73%; Fig. 2h), but bias was insignificant (Fig. 4

and Supplementary Tables 1–15). DISCUSSION The principal finding of the present study is that the achievement of a DBP of <80 mmHg in the drug-intervention group is associated with a

significant reduction in coronary revascularization and heart failure but does not increase all-cause death and cardiovascular death when the achieved SBP is ≤130 mmHg. A systematic review

of the effects of reducing SBP was conducted by Bangalore et al. including 15 RCTs involving CAD patients not having heart failure and acute myocardial infarction, who were randomized to

antihypertensive drugs or placebo [13]. The intensive SBP reduction with an achieved SBP of 131–135 mmHg was associated with a 15% decrease in heart failure and a 10% decrease in stroke but

at the expense of hypotension, when compared with the standard SBP reduction with an achieved SBP of 136–140 mmHg. Moreover, a more intensive SBP reduction achieving an SBP of  ≤130 mmHg was

associated with greater reductions in heart failure and stroke (27 and 17%, respectively) as well as borderline reductions in myocardial infarction and angina pectoris, when compared with

the standard SBP reduction, while not affecting all-cause death and cardiovascular death. These findings might provide a rationale supporting the setting of an SBP target in CAD patients

down to  <130 mmHg in the recent 2017 ACC/AHA guidelines [11]. However, this systematic review did not mention the effects of the achieved DBP ranges on the outcomes. Because the RCTs,

which investigated the effects of the achieved DBP ranges on the outcomes, were not found using a systematic search, we performed a systematic review of RCTs examining the effects of

reducing DBP in CAD patients who were randomized to antihypertensive drugs or placebo. Of note, all seven RCTs we included in our study are included in the meta-analysis by Bangalore et al.,

as mentioned above [13]. Indeed, the achieved SBP was 126.3 mmHg in the drug-intervention group and 131.5 mmHg in the placebo-control group in our study (Table 1). Our meta-analysis showed

that the achievement of a DBP < 80 mmHg was associated with an 11% reduction in coronary revascularization and a 31% reduction in heart failure (Fig. 2). We could not perform a

meta-analysis of the effects on renal failure because only the EUROPA trial reported the incidence of renal failure among seven RCTs [18]. An intervention group with a DBP < 75 mmHg,

including the four RCTs of CAMELOT-E [17], IMAGINE [19], PART-2 [20] and PEACE [21], was associated with a 22% reduction in heart failure and no increase in total death, cardiovascular

death, myocardial infarction, revascularization, or stroke (Fig. 3). Thus, it is important to note that controlling DBP to less than 80 or even 75 mmHg can prevent heart failure in patients

with CAD. The identified seven RCTs (DBP < 80 mmHg) used calcium-channel blockers and ACE inhibitors in the intervention group, and only ACE inhibitors were used in the four intensive

RCTs (DBP < 75 mmHg). This fact might be interesting given that calcium-channel blockers directly dilate the coronary artery while ACE inhibitors can improve autoregulation in the

coronary artery [23]. The J-curve phenomenon has been reported, especially in post-hoc analysis and observational studies. Coronary revascularization reduced the rate of primary outcome

(all-cause death, nonfatal myocardial infarction or nonfatal stroke) by half in the group achieving DBP < 60 mmHg in the INVEST study [24]. Another post-hoc analysis of the INVEST trial

showed that the relation between cardiovascular outcome and DBP was linear in patients with CAD and revascularization by coronary artery bypass grafting (CABG), and the lowest event rates

were observed in patients with a DBP of 125/55 mmHg [25]. The authors concluded that a more complete revascularization can attenuate hypoperfusion at a low DBP [25]. Therefore, it seems that

severe coronary lesions, which need revascularization, contribute to the increased rate of primary outcome at a low DBP. After total coronary revascularization, there is no reason to

hesitate to decrease DBP down to 80 mmHg. Indeed, in the Japan CREDO-Kyoto registry, a DBP ≤ 70 mmHg was not found to be an independent risk factor for cardiovascular death in patients with

CAD after revascularization [26]. A higher event rate was not observed in patients older than 75 years, even in those with a DBP < 60 mmHg [27]. Importantly, no RCT has been performed

that enables us to evaluate the effect of a DBP less than 70 mmHg in CAD patients. Further RCT studies targeting a DBP less than 70 mmHg are necessary. STUDY LIMITATIONS None of the trials

were designed to compare different DBP target levels. In seven RCTs, calcium antagonists and ACE inhibitors were used. Interestingly, only ACE inhibitors were used in trials that achieved

DBP levels <75 mmHg in the intervention group. Thus, we could not compare differences relating to the types of antihypertensive agents used in this meta-analysis. CONCLUSIONS The present

study showed that the achievement of a DBP < 80 mmHg significantly reduces coronary revascularization and heart failure but at the expense of causing hypotension in CAD patients with an

achieved SBP < 130 mmHg. We should not hesitate to target SBP down to 130 mmHg in patients with CAD when we observe DBP values of down to 80 mmHg, which are tolerable. Our results can

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Article  CAS  Google Scholar  Download references AUTHOR INFORMATION Author notes * These authors contributed equally: Ryuji Okamoto, Eita Kumagai AUTHORS AND AFFILIATIONS * Department of

Cardiology and Nephrology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan Ryuji Okamoto & Masaaki Ito * Division of Cardiovascular Medicine,

Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan Eita Kumagai & Yoshihiro Fukumoto * Department of Cardiology,

Kurume University Medical Center, 155-1 Kokubu-machi, Kurume, Fukuoka, 839-0863, Japan Hisashi Kai * Department of Advanced Cardiovascular Therapeutics, Nagoya University Graduate School of

Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan Rei Shibata * Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi,

Higashi-ku, Fukuoka, 812-8582, Japan Toshio Ohtsubo * Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501,

Japan Hiroaki Kawano * Divition of Nephrology and Hypertension, Yokohama City University Medical Center, 4-57 Urafune-cho, Minami-ku, Yokohama, 232-0024, Japan Akira Fujiwara * Department of

Preventive Medicine and Public Health, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, Fukuoka, 814-0180, Japan Hisatomi Arima Authors * Ryuji Okamoto View author publications You

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author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Ryuji Okamoto. ETHICS DECLARATIONS CONFLICT OF INTEREST The Department of Cardiology and Nephrology, Mie University

Graduate School of Medicine, received research grants from Bristol-Myers Squibb, MSD K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo

Pharmaceutical Co., Ltd., Genzyme Japan, Shionogi & Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Corporation, Otsuka Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd.,

AstraZeneca K.K., and Boehringer Ingelheim Co., Ltd. Rei Shibata received honoraria from Medtoronic, Boehringer Ingelheim, Eli Lilly and Mitsubishi Tanabe Pharma. Toshio Ohtsubo received

lecture fees from Sanwa Kagaku Kenkyusho Co., Ltd. Hisashi Kai received lecture fees from Daiichi Sankyo Co Pharmaceutical Co., Ltd., Mitsubishi Tanabe Corporation, Shionogi & Co., Ltd.,

Sumitomo Dainippon Pharma Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Masaaki Ito received lecture fees from Daiichi Sankyo Co Pharmaceutical Co., Ltd., Mitsubishi Tanabe Corporation,

Bayer Yakuhin, Ltd. and Takeda Pharmaceutical Co., Ltd. ADDITIONAL INFORMATION PUBLISHER’S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and

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ARTICLE CITE THIS ARTICLE Okamoto, R., Kumagai, E., Kai, H. _et al._ Effects of lowering diastolic blood pressure to <80 mmHg on cardiovascular mortality and events in patients with

coronary artery disease: a systematic review and meta-analysis. _Hypertens Res_ 42, 650–659 (2019). https://doi.org/10.1038/s41440-018-0189-z Download citation * Received: 17 August 2018 *

Revised: 07 October 2018 * Accepted: 09 October 2018 * Published: 05 April 2019 * Issue Date: May 2019 * DOI: https://doi.org/10.1038/s41440-018-0189-z SHARE THIS ARTICLE Anyone you share

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Nature SharedIt content-sharing initiative KEYWORDS * Coronary artery disease * diastolic blood pressure * hypertension * J curve * meta-analysis