Effects of Intensive Blood Pressure Lowering on Cardiovascular and Renal Outcomes: A Systematic Review and Meta-Analysis.


Guidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebo-controlled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes.

Methods and Findings

We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels.

We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%–21%), 13% for myocardial infarction (0%–25%), 24% for stroke (8%–37%), and 11% for end stage kidney disease (3%–18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%–16%), and a trend towards benefit for retinopathy (19%, 0%–34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years).

Conclusions

Intensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data.

Discussion

This meta-analysis, including more than 37,000 individuals amongst whom over 1,900 major vascular events were recorded, demonstrates a clear vascular benefit for more intensive BP lowering regimens aiming for lower BP targets. Major cardiovascular events were reduced by 11% and serious renal outcomes by 11% with specific benefit for a broad range of cardiovascular and renal outcomes, including myocardial infarction, stroke, albuminuria, and ESKD. However, there was no evidence to suggest that intensive BP treatment reduced or increased the risk of cardiovascular or noncardiovascular mortality. To the extent that it was possible to explore them, the observed beneficial effects did not appear to be attenuated by any characteristics of the patients involved or the BP regimens tested. Some adverse effects were more common in the intensively treated groups, but there was no suggestion that more intensive regimens were likely to result in net harm. In addition, the targets used in the most intensive BP control strategies were not associated with adverse cardiovascular outcomes or increased rates of death.

The findings from this overview are consistent with a recent analysis in patients with diabetes [37] but contrast with reports from some individual studies [16],[18] and a recent meta-analysis that have suggested no benefit from more intensive BP lowering regimens [15]. In both cases the most likely reason for this is the limited statistical power of the prior analyses. Few of the individual trials have recorded sufficient numbers of events and achieved large enough BP differences between randomized groups, to detect the most plausible effects of intensive BP control regimens on vascular outcomes. This is particularly so for the outcome of myocardial infarction, which is less strongly associated with BP than stroke, and therefore requires a much larger body of data to detect the anticipated effects. The prior much cited overview [15] had similar problems because the selective inclusion criteria, addressing a very narrow clinical question, meant that much applicable evidence was excluded. In this report, we approximately doubled the numbers of participants and events available for analysis, in large part because we were able to include new data from three large trials [16][18].

Key to interpreting the plausibility of the new findings presented here is an understanding of the broader clinical and epidemiological context. Associations observed in cohort studies and risk reductions seen in clinical trials of BP lowering versus control both provide indications of the magnitude of benefit that might be anticipated as a consequence of the 7.5/4.5-mmHg difference in BP seen in the current set of trials. The very close concordance between the expected benefits and those observed in this meta-analysis provides strong support for the validity of the current findings and argues for their wider generalisability.

It is now widely acknowledged that the observational association of BP with risk is direct and continuous to levels of BP far below the usual definition of hypertension [1][3]. Reported J-curve associations, seen mostly amongst patients with established disease, are likely to be attributable mostly to “reverse causation”—low BP is caused by the disease (e.g., prior heart attack) [38] and is associated with an increased risk of a poor outcome, but is not in itself the cause of the poor outcome. A number of recent post hoc analyses of clinical trial datasets have reignited concerns about the possibility of a J-curve for coronary disease at achieved systolic BP levels below 120 mmHg [39][41]. However, these analyses are nonrandomised in nature and need to be considered in light of the potential for confounding. The consistency of benefit at different baseline and achieved BP levels in this and other systematic reviews of all available evidence [4] suggests that confounding is indeed the reason for these observations.

We found evidence of benefit for clinically important microvascular outcomes with intensive BP lowering strategies. Specifically, the risk of ESKD was reduced by 11%. Similarly, trials in people with diabetes showed evidence of a reduced incidence of microalbuminuria and a trend towards a reduced incidence of retinopathy. Taken together, these results provide substantial reassurance about the renal safety of intensive BP lowering and suggest benefit for microvascular outcomes is likely.

The present overview did not provide especially clear evidence about the effects of more intensive BP control on side effects because the quantity of available data was limited. Adverse events and serious adverse events were not increased overall, but an increased frequency of hypotension was observed. Of note, absolute rates of serious side effects appeared to be low and infrequently led to discontinuation of the intensive BP lowering strategy, although reporting of these events was suboptimal so some caution must be exercised in interpreting these results. These findings would suggest that lower targets for BP are likely to be achievable for many individuals and that there would be significant net benefit to population health if the strategy were widely implemented, although more precise data regarding the totality of adverse outcomes would be important in clarifying the remaining uncertainty in this regard.

This overview benefits from the rigorous methodology used, the homogeneity of the individual trial results summarized by the meta-analyses, and the consistent effects observed across a range of macro- and microvascular disease outcomes. All serve to provide reassurance about the likely validity of the primary conclusions. Chief among the limitations are the moderate number and size of trials available, the heterogeneity of participants in included trials, and in particular the few data to describe directly the effects of intensive BP lowering amongst individuals with uncomplicated hypertension. Most trials included in this study included participants with additional cardiovascular risk factors, including diabetes or CKD, which also limits the generalisability of the findings. Additionally, the subgroup analyses are based on the study characteristics rather than individual patient data (IPD). An IPD meta-analysis would provide important additional information. Finally, although this analysis suggests that BP targets at 130/80 or lower are likely to produce additional overall benefit, there is insufficient data to confirm a specific BP threshold. These analyses gain from the inclusion of analyses of renal outcomes. With ageing of the population, CKD is becoming an increasingly large cause of disease burden and documenting the effects on hard renal outcomes is central to estimating the overall balance of risks and benefits.

A range of research questions arise from this work, perhaps most importantly how best to achieve and maintain greater BP reductions in high-risk patients, particularly given the relatively modest BP differences between the randomized groups achieved on average in the completed trials. Large and rapid reductions may be less well tolerated, particularly if hypertension has been severe and longstanding, but the optimal ways to achieve this while maintaining adherence are still uncertain. It is apparent that low-dose combinations will be an important part of this solution  but other approaches to improve treatment rates and adherence will be required.

In conclusion, these overviews provide support for clinical guidelines advocating more intensive BP lowering amongst high-risk patient groups, although the limitations of the available data mean that the results should be generalized with some caution. Whilst few large-scale randomized trials have been done to evaluate the effects of intensive BP lowering amongst patients with uncomplicated hypertension, and more data would clearly be helpful in defining the groups most likely to benefit as well as to suffer adverse effects, the totality of the current evidence suggests that benefits are likely to be greater than harms. BP lowering to below current thresholds may achieve additional benefits and reduce the burden of cardiovascular morbidity and mortality for many patients. If our data are applied to hypertensive patients at high cardiovascular risk with an annual cardiovascular event rate of about 2%, the available data suggest that among every thousand such people, intensive BP lowering could prevent two of the 20 cardiovascular events expected to occur each year, while increasing one severe hypotension event.

Source: PLOS

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