Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis

Abstract

Aims: This meta-analysis aims to quantify the association of reduced coronary flow with all-cause mortality and major adverse cardiovascular events (MACE) across a broad range of patient groups and pathologies.

Methods and results: We systematically identified all studies between 1 January 2000 and 1 August 2020, where coronary flow was measured and clinical outcomes were reported. The endpoints were all-cause mortality and MACE. Estimates of effect were calculated from published hazard ratios (HRs) using a random-effects model. Seventy-nine studies with a total of 59 740 subjects were included. Abnormal coronary flow reserve (CFR) was associated with a higher incidence of all-cause mortality [HR: 3.78, 95% confidence interval (CI): 2.39-5.97] and a higher incidence of MACE (HR 3.42, 95% CI: 2.92-3.99). Each 0.1 unit reduction in CFR was associated with a proportional increase in mortality (per 0.1 CFR unit HR: 1.16, 95% CI: 1.04-1.29) and MACE (per 0.1 CFR unit HR: 1.08, 95% CI: 1.04-1.11). In patients with isolated coronary microvascular dysfunction, an abnormal CFR was associated with a higher incidence of mortality (HR: 5.44, 95% CI: 3.78-7.83) and MACE (HR: 3.56, 95% CI: 2.14-5.90). Abnormal CFR was also associated with a higher incidence of MACE in patients with acute coronary syndromes (HR: 3.76, 95% CI: 2.35-6.00), heart failure (HR: 6.38, 95% CI: 1.95-20.90), heart transplant (HR: 3.32, 95% CI: 2.34-4.71), and diabetes mellitus (HR: 7.47, 95% CI: 3.37-16.55).

Conclusion: Reduced coronary flow is strongly associated with increased risk of all-cause mortality and MACE across a wide range of pathological processes. This finding supports recent recommendations that coronary flow should be measured more routinely in clinical practice, to target aggressive vascular risk modification for individuals at higher risk.

Keywords: Cardiology; Cardiovascular risk; Coronary flow reserve; Interventional; Microvascular disease.

Graphical Abstract

The association of coronary flow reserve with risk of death and major adverse cardiovascular events. HR, hazard ratio.

Figure 1

Search strategy and source of included studies. CFR, coronary flow reserve.

Figure 2

Coronary flow reserve and risk of death and major adverse cardiovascular events. All hazard ratios expressed after multivariable-adjusted analysis. Hazard ratios shown for the outcomes for which there are sufficient published data (i.e. at least two studies). Hazard ratios are represented by squares, and 95% confidence intervals are represented by horizontal lines.

Figure 3

Forest plot showing coronary flow reserve as an indicator of all-cause mortality. Hazard ratios for individual studies are represented by squares, and 95% confidence intervals (CI) are represented by horizontal lines. Pooled estimates and their 95% confidence intervals are represented by diamonds. Subgroups are by disease presentation. The sizes of the squares and the diamonds are proportional to the weight assigned to the relative effect sizes.

Figure 4

Forest plot showing coronary flow reserve as an indicator of major adverse cardiovascular events. Hazard ratios for individual studies are represented by squares, and 95% confidence intervals are represented by horizontal lines. Pooled estimates and their 95% confidence intervals are represented by diamonds. Subgroups are by disease presentation. The sizes of the squares and the diamonds are proportional to the weight assigned to the relative effect sizes.

Figure 5

Forest plot showing coronary flow reserve as an indicator of mortality in patients with ischaemic heart disease. Hazard ratios for individual studies are represented by squares, and 95% confidence intervals are represented by horizontal lines. Subgroups are by disease presentation. Pooled estimates and their 95% confidence intervals are represented by diamonds. The sizes of the squares and the diamonds are proportional to the weight assigned to the relative effect sizes.

Figure 6

Forest plot showing the index of microcirculatory resistance as an indicator of major adverse cardiovascular events. Hazard ratios for individual studies are represented by squares, and 95% confidence intervals are represented by horizontal lines. Pooled estimates and their 95% confidence intervals are represented by diamonds. Subgroups are by disease presentation. The sizes of the squares and the diamonds are proportional to the weight assigned to the relative effect sizes. NSTEMI, non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction.

Figure 7

Forest plot showing coronary flow reserve as an indicator of mortality—subgroup analysis by measurement modality. Hazard ratios for individual studies are represented by squares, and 95% confidence intervals are represented by horizontal lines. Pooled estimates and their 95% confidence intervals are represented by diamonds. The sizes of the squares and the diamonds are proportional to the weight assigned to the relative effect sizes. CMR, cardiac magnetic resonance; PET, positron emission tomography.

Figure 8

Forest plot showing coronary flow reserve as an indicator of major adverse cardiovascular events—subgroup analysis by measurement modality. Hazard ratios for individual studies are represented by squares, and 95% confidence intervals are represented by horizontal lines. Pooled estimates and their 95% confidence intervals are represented by diamonds. The sizes of the squares and the diamonds are proportional to the weight assigned to the relative effect sizes. CMR, cardiac magnetic resonance; PET, positron emission tomography.