Description of studies
Results of the search
The search identified 597 records. There remained 235 publications after partial screen and removal of duplicates by Trials Research Coordinator. Most of those publications were rejected after reading the abstract or the complete report. This left 11 references that seemed appropriate for this systematic review (Figure 1). The detailed analysis of those 11 publications revealed:
- 5 randomized controlled trials from 6 publications that met the inclusion criteria
- 5 randomized controlled trials that did not meet the inclusion criteria
One trial (ACCORD BP 2010) compared clinical outcomes associated with different systolic blood pressure (SBP) targets within our definitions for ‘lower’ and ‘standard’ targets. Four trials (ABCD-H 1998, ABCD-N 2002, ABCD-2V 2006, and the subgroup of people with diabetes in HOT 1998) compared clinical outcomes associated with different diastolic blood pressure (DBP) targets meeting our definitions for ‘lower’ and ‘standard’ targets
The 5 included trials were randomized and open label. In each trial an independent end point committee, which was blinded to the study intervention arms, reviewed all cardiovascular events.
In ACCORD BP 2010 the participants were also randomly assigned (in a 2-by-2 factorial design) to either intensive or standard glycemic control (the ACCORD glycemia trial). In HOT 1998 the participants were also randomly assigned in a factorial design to receive aspirin or placebo.
The follow-up period varied from 1.9 to 5 years.
ACCORD BP 2010 was conducted in the United States and Canada. HOT 1998 included participants from 26 countries from Europe, Asia, North and South America.
The inclusion criteria varied among the trials (see table of characteristics of included studies). ACCORD BP 2010, ABCD-H 1998, ABCD-N 2002, and ABCD-2V 2006 only included people with type 2 diabetes. The type of diabetes was not specified in HOT 1998. ACCORD BP 2010 also required a high cardiovascular risk, defined by already established cardiovascular disease, evidence of subclinical cardiovascular disease, or at least two additional risk factors for cardiovascular disease.
The baseline blood pressure required for inclusion also varied. ACCORD BP 2010 required a systolic blood pressure between 130 and 180 mmHg when taking three or fewer antihypertensive medications to be included. Participants in ABCD-H 1998 had a baseline diastolic blood pressure equal to or higher than 90 mm Hg. Participants in ABCD-N 2002 had a baseline diastolic blood pressure between 80 and 89 mmHg and were not receiving antihypertensive medications at the randomization visit, but some of them had elevated systolic blood pressure. ABCD-2V 2006 included people with a systolic BP lower than 140 mmHg, and a diastolic BP between 80 and 90 mmHg. In HOT 1998 the baseline diastolic blood pressure was between 100 mmHg and 115 mmHg.
The trials included people between the ages of 40 and 81 years. The number of participants included in each study was: ABCD-2V 2006: 129 participants; ABCD-H 1998: 470 participants; ABCD-N 2002: 480 participants; ACCORD BP 2010: 4733 participants; HOT 1998: 1501 participants.
Participants in ACCORD BP 2010 were randomly assigned to intensive therapy that targeted systolic blood pressure of less than 120 mmHg, or standard therapy that targeted systolic blood pressure of less than 140 mmHg.
Participants in ABCD-H 1998 and ABCD-2V 2006 were randomized into two treatment arms consisting of ‘intensive’ treatment with a diastolic blood pressure goal of 75 mmHg, and ‘moderate’ treatment with a diastolic blood pressure goal of 80-89 mmHg.
Participants in ABCD-N 2002 were randomized into two treatment arms consisting of "intensive" or "moderate" treatment. The goal in the "intensive" treatment group was to achieve a decrease of 10 mmHg below baseline in diastolic blood pressure (i.e. 70 to 79 mmHg), whereas the goal in the "moderate" treatment group was to maintain a diastolic blood pressure between 80 and 89 mmHg.
Participants in HOT 1998 were randomly assigned to one of three diastolic blood pressure target groups: less than or equal to 90 mmHg, less than or equal to 85 mmHg, or less than or equal to 80 mmHg.
In ABCD-H 1998 and ABCD-N 2002 the initial antihypertensive agent was either nisoldipine or enalapril, randomly assigned in a factorial way. Valsartan was the initial antihypertensive medication in ABCD-2V 2006, following a established drug procedure afterwards. In HOT 1998 felodipine was given as baseline therapy with the addition of other agents according to a five-step regimen. No specific drug procedure was decribed in ACCORD BP 2010.
In ABCD-N 2002 and ABCD-2V 2006 participants assigned to the ‘standard’ therapy groups were given placebo initially.
Several types of major cardiovascular events were the primary outcomes in ACCORD BP 2010 and HOT 1998. Surrogate markers of renal function were the primary outcome in the ABCD trials (ABCD-2V 2006, ABCD-H 1998, ABCD-N 2002) and some types of cardiovascular events were reported as secondary outcomes.
e. Additional notes:
The ACCORD BP 2010 trial was sponsored by the National Heart, Lung, and Blood Institute (NHLBI) from the United States. The remaining trials were supported by pharmaceutical companies.
ACCORD BP 2010 was conducted between January 2001 and October 2005. HOT was conducted between October 1992 and August 1997. The dates for the other trials were not specified.
United Kingdom Prospective Diabetes Study ( UKPDS 38 1998)
This study was excluded because the target for systolic blood pressure in the 'tight control' group was higher than stated in our protocol. In addition, and more importantly, the targets for both systolic and diastolic blood pressure in the 'less tight control' group were much higher than specified in the protocol for this systematic review.
Hypertension in Diabetes Study IV ( HDS 1996 )
This trial was excluded from the review for the same reasons as the UKPDS 38 trial. Furthermore, it is likely that participants in this trial represent a subgroup of participants included in UKPDS 38, because the study design is similar and the authors are the same.
SANDS ( SANDS 2008 )
This trial was not included because the dual intervention would not allow us to address the events specifically associated with a lower blood pressure target. Besides, both systolic blood pressure targets in this trial were within the values considered as 'lower targets' in our systematic review.
Lewis et al (Lewis 1999)
It was excluded because it did not provide data on any of the outcomes defined for this systematic review.
Steno-2 study ( Steno-2 2003 )
This trial was not included because the multifactorial intervention prevented any inference as to whether any difference in clinical outcomes could be attributed to a lower blood pressure target or to any of the other combined interventions.
Effects of interventions
See: Summary of findings for the main comparison
1. Systolic blood pressure target
Only one randomized trial (ACCORD BP 2010) was identified comparing targets for systolic blood pressure within the definitions established for this review. The data were obtained from the main report of the trial and the published appendices.
1.1 Total mortality
There was no difference in total mortality between the two blood pressure target groups: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.84 to 1.30, P = 0.69 (Analysis 1.1).
1.2 Cardiovascular (CV) mortality
There was no difference in cardiovascular mortality between the two blood pressure target groups: RR 1.04, 95% CI 0.73 to 1.48, P = 0.84 (Analysis 1.2).
1.3 Non-CV mortality
There was no difference in non-cardiovascular mortality between the two blood pressure target groups: RR 1.05, 95% CI 0.79 to 1.40, P = 0.74 (Analysis 1.3).
1.4 Total serious adverse events
The total number of serious adverse events was not reported in the ACCORD BP 2010 trial. We calculated the sum of total mortality, non-fatal myocardial infarction, non-fatal stroke, non-fatal heart failure, end-stage renal disease or need for dialysis, and other serious adverse events attributed to blood pressure medications. There was no difference in the calculated total serious adverse events between the two blood pressure target groups: RR 1.01, 95% CI 0.91 to 1.13, P = 0.81 (Analysis 1.4).
1.5 Myocardial infarction
There were 133 myocardial infarctions (126 non-fatal) in the intensive therapy group and 151 (146 non-fatal) in the standard therapy group, with no significant difference between the groups: RR 0.88, 95% CI 0.71 to 1.11, P = 0.28 (Analysis 1.5).
There were 36 strokes (34 non-fatal) in the intensive therapy group and 62 (55 non-fatal) in the standard therapy group. The difference between the groups was statistically significant: RR 0.58, 95% CI 0.39 to 0.88, P = 0.009, absolute risk reduction 1.1% (Analysis 1.6).
1.7 Congestive heart failure
There was no difference in fatal or non-fatal heart failure between the two blood pressure target groups: RR 0.93, 95% CI 0.69 to 1.24, P = 0.60 (Analysis 1.7).
1.8 End-stage renal failure
There was no difference in end-stage renal failure or need for dialysis between the two blood pressure target groups: RR 1.02, 95% CI 0.71 to 1.46, P = 0.84 (Analysis 1.8).
1.9 All other serious adverse events
The ACCORD BP 2010 investigators reported separately other serious adverse events attributed to blood pressure medications, including hypotension, syncope, bradycardia or arrhythmia, hyperkalemia, angioedema, and renal failure. These serious adverse events were significantly more prevalent in the 'intensive therapy' group: RR 2.58, 95% CI 1.70 to 3.91, P < 0.00001, absolute risk increase 2.0% (Analysis 1.9).
1.10 Systolic blood pressure achieved
After the first year of therapy, the average systolic blood pressure achieved was significantly lower in the 'intensive therapy' group, mean difference 14.2 mmHg, P < 0.00001 (119.3 mmHg vs 133.5 mmHg in the 'intensive' vs the 'standard' groups respectively; Analysis 1.10).
1.11 Diastolic blood pressure achieved
After the first year of therapy, the average diastolic blood pressure achieved was significantly lower in the 'intensive therapy' group, mean difference 6.1 mmHg, P < 0.00001 (64.4 mmHg vs 70.5 mmHg in the 'intensive' vs the 'standard' groups respectively; Analysis 1.11).
1.12 Withdrawals due to adverse events
There is no information available.
1.13 Number of antihypertensive drugs used
The mean number of antihypertensive drugs used after the first year was significantly greater in the 'intensive therapy' group (3.4 vs 2.1), P < 0.00001; Analysis 1.13.
2. Diastolic blood pressure (DBP) target
Three trials compared clinical outcomes associated with different diastolic blood pressure targets specifically in people with diabetes (ABCD-H 1998; ABCD-N 2002; ABCD-2V 2006). Although it enrolled non-diabetic participants, the HOT 1998 trial could be included in this analysis because it reported outcomes in the subgroup of participants with diabetes separately. Some outcomes, not provided in the published reports of the trials, were obtained from the Blood Pressure Lowering Treatment Trialists` Collaboration (BPLTTC 2003).
Several issues regarding the design and the characteristics of these trials must be mentioned before analyzing the results:
a. Regarding baseline characteristics, if the three ABCD trials are combined, a significantly greater proportion of participants randomized to 'standard target' had established cardiovascular or cerebrovascular disease compared with the 'lower target' group (41.0% vs 33.5%, P = 0.007). This difference in baseline characteristics is important and would be expected to have an impact on the clinical outcomes against the 'standard target' group, because having a greater proportion of participants with established vascular disease increases the risk of having future events. The magnitude of this potential bias is increased by the fact that the ABCD trials account for 42% of the total number of participants included in the analysis for diastolic BP targets.
In the HOT 1998 trial, randomization was blocked for several factors, including diabetes mellitus, and therefore it is possible that baseline characteristics of participants with diabetes were similar between the target blood pressure groups, but the details are not available and therefore the potential for bias also exists for this trial.
b. In terms of inclusion criteria, the ABCD-N 2002 and ABCD-2V 2006 trials included only normotensive diabetic participants, defined as having a diastolic blood pressure between 80 and 89 mmHg. Twenty-six participants (5.4%) with isolated systolic hypertension (systolic blood pressure greater than 160 mmHg and diastolic blood pressure between 80 and 89 mmHg) were enrolled in ABCD-N 2002 during the first year of recruitment, but none thereafter. On the other hand, ABCD-H 1998 and HOT 1998 only included participants with elevated blood pressure, but the criteria for inclusion were different. In ABCD-H 1998 participants had a baseline diastolic blood pressure equal to or higher than 90 mmHg, whereas an inclusion criterion in HOT 1998 was a baseline diastolic blood pressure between 100 and 115 mmHg.
c. When the HOT 1998, ABCD-H 1998 and ABCD-N 2002 trials were conducted, the diagnostic criteria for diabetes mellitus were different from those currently used. At that time, diabetes mellitus was defined as two fasting plasma glucose levels, measured on different days, higher than 7.7 mmol/L (140 mg/dL), instead of 7.0 mmol/L (126 mg/dL), as currently defined.
2.1 Total mortality
The data on mortality from ABCD-H 1998 deserve an explanation. The first publication of the trial (ABCD-H 1998) mentioned 30 death in total, but it did not provide details on the distribution according to blood pressure targets. Later publications stated that “patients randomized to intensive therapy had a lower incidence of all-cause mortality when compared to moderate therapy, 5.5% vs 10.7%, p= 0.037” (ABCD-H 2000; ABCD 2007), without providing absolute numbers. Given that 237 participants were assigned to the intensive treatment group, and 233 participants to the moderate treatment group, the absolute number of deaths calculated from the reported percentages would be 13 and 25 respectively, for a total of 38 deaths, which differs from the total mortality mentioned in the first report. Finally, the Blood Pressure Lowering Treatment Trialists`Collaboration reported 32 deaths in the same trial, 10 in the intensive treatment group and 22 in the moderate treatment group (BPLTTC 2003). Due to the lack of concordance, the information from the BPLLTTC was used for this analysis, because it was the only one providing absolute numbers and because they were closer to the figures mentioned in the original report.
There was a statistically non-significant trend toward reduced risk of total mortality in the 'lower target' group: RR 0.73, 95% CI 0.53 to 1.01, P = 0.05 (Analysis 2.1).
2.2 Cardiovascular mortality
There was no difference in cardiovascular mortality between the '''lower target' and the 'standard target' groups: RR 0.79, 95% CI 0.52 to 1.19, P = 0.26 (Analysis 2.2).
2.3 Non-CV mortality
There was no difference in non-cardiovascular mortality in the 'lower target' compared with the 'standard target' group: RR 0.62, 95% CI 0.36 to 1.06, P = 0.08 (Analysis 2.3).
2.4 Total serious adverse events
Total serious adverse events were not reported in any of the trials.
2.5 Myocardial infarction
There was no difference in the incidence of myocardial infarction between the 'lower target' and the 'standard target' groups: RR 0.95, 95% CI 0.64 to 1.40, P = 0.79 (Analysis 2.5).
There was no difference in the incidence of stroke in the 'lower target' compared with the 'standard target' group, RR 0.67, 95% CI 0.42 to 1.05), P = 0.08 (Analysis 2.6).
2.7 Congestive heart failure
Data on this outcome from the subgroup of participants with diabetes included in HOT 1998 and the ABCD-2V 2006 trial are not available. Data from ABCD-H 1998 were provided by BPLTTC. There was no difference in the incidence between the two treatment target groups: RR 1.06, 95% CI 0.58 to 1.92, P = 0.86 (Analysis 2.7).
2.8 End-stage renal failure
End-stage renal failure was not reported in any of the trials.
2.9 All other serious adverse events
All other serious adverse events were not reported in any of the trials.
2.10 Systolic blood pressure achieved
No information is available from the subgroup of participants with diabetes in HOT 1998. The average systolic blood pressure achieved in the ABCD trials was significantly lower in the 'lower target' group, mean difference 7.31 mmHg, P < 0.00001 (mean SBP = 128 mmHg vs 135 mmHg in the 'lower target' vs the 'standard target' groups respectively; Analysis 2.10).
2.11 Diastolic blood pressure achieved
No information is available from the subgroup of participants with diabetes in HOT 1998. The average diastolic blood pressure achieved in the ABCD trials was significantly lower in the 'lower target' group, mean difference 6.85 mmHg, P < 0.00001 (mean DBP= 76 mmHg vs 83 mmHg in the 'lower target' vs the 'standard target' groups respectively; Analysis 2.11).
2.12 Withdrawals due to adverse effects
Withdrawals due to adverse events were not reported in any of the trials.
2.13 Number of antihypertensive drugs used
The number of antihypertensive drugs used was not reported in any of the trials.
Sensitivity analysis for diastolic blood pressure < 80 mm Hg vs < 90 mm Hg
Because clinical guidelines recommend a diastolic blood pressure target lower than 80 mmHg, we decided to perform a sensitivity analysis in trials comparing a target of lower than 80 mmHg versus the standard target of lower than 90 mmHg. This sensitivity analysis only excluded the treatment arm lower than 85 mmHg from the HOT 1998 trial. It therefore has the same limitations described for the entire analysis on DBP, except that in this case the unbalance in baseline characteristics against the standard target from the ABCD trials has a more pronounced effect because they represent more than 50% of the total population.
The results from this sensitivity analysis are shown in the following table. They are very similar to the entire analysis for DBP mentioned above. In this case the reduction in total mortality associated with the lower target achieved statistical significance. The contributions from both cardiovascular and non-CV mortality were numerically similar.
|Outcome||Studies||Participants||Statistical method||Effect estimate||P|
|Total mortality||4||2079||Risk Ratio (M-H, Fixed, 95% CI)||0.64, 95% CI 0.45 to 0.92||0.02|
|Cardiovascular mortality||3||1950||Risk Ratio (M-H, Fixed, 95% CI)||0.64, 95% CI 0.39 to 1.03||0.07|
|Non-cardiovascular mortality||3||1950||Risk Ratio (M-H, Fixed, 95% CI)||0.62, 95% CI 0.35 to 1.08||0.09|
|Total serious adverse events||0||0||Risk Ratio (M-H, Fixed, 95% CI)||Not estimable|| |
|Myocardial infarction||4||2079||Risk Ratio (M-H, Fixed, 95% CI)||0.98, 95% CI 0.65 to 1.48||0.93|
|Stroke||4||2079||Risk Ratio (M-H, Fixed, 95% CI)||0.64, 95% CI 0.39to 1.06||0.08|
|Congestive heart failure||2||950||Risk Ratio (M-H, Fixed, 95% CI)||1.06, 95% CI 0.58 to 1.92||0.86|