Gradual Versus Abrupt Reperfusion During Primary Percutaneous Coronary Interventions in ST-Segment-Elevation Myocardial Infarction (GUARD)

Abstract

Background Intramyocardial edema and hemorrhage are key pathological mechanisms in the development of reperfusion-related microvascular damage in ST-segment-elevation myocardial infarction. These processes may be facilitated by abrupt restoration of intracoronary pressure and flow triggered by primary percutaneous coronary intervention. We investigated whether pressure-controlled reperfusion via gradual reopening of the infarct-related artery may limit microvascular injury in patients undergoing primary percutaneous coronary intervention. Methods and Results A total of 83 patients with ST-segment-elevation myocardial infarction were assessed for eligibility and 53 who did not meet inclusion criteria were excluded. The remaining 30 patients with totally occluded infarct-related artery were randomized to the pressure-controlled reperfusion with delayed stenting (PCRDS) group (n=15) or standard primary percutaneous coronary intervention with immediate stenting (IS) group (n=15) (intention-to-treat population). Data from 5 patients in each arm were unsuitable to be included in the final analysis. Finally, 20 patients undergoing primary percutaneous coronary intervention who were randomly assigned to either IS (n=10) or PCRDS (n=10) were included. In the PCRDS arm, a 1.5-mm balloon was used to achieve initial reperfusion with thrombolysis in myocardial infarction grade 3 flow and, subsequently, to control distal intracoronary pressure over a 30-minute monitoring period (MP) until stenting was performed. In both study groups, continuous assessment of coronary hemodynamics with intracoronary pressure and Doppler flow velocity was performed, with a final measurement of zero flow pressure (primary end point of the study) at the end of a 60-minute MP. There were no complications associated with IS or PCRDS. PCRDS effectively led to lower distal intracoronary pressures than IS over 30 minutes after reperfusion (71.2±9.37 mm Hg versus 90.13±12.09 mm Hg, P=0.001). Significant differences were noted between study arms in the microcirculatory response over MP. Microvascular perfusion progressively deteriorated in the IS group and at the end of MP, and hyperemic microvascular resistance was significantly higher in the IS arm as compared with the PCDRS arm (2.83±0.56 mm Hg.s.cm^-1 versus 1.83±0.53 mm Hg.s.cm^-1, P=0.001). The primary end point (zero flow pressure) was significantly lower in the PCRDS group than in the IS group (41.46±17.85 mm Hg versus 76.87±21.34 mm Hg, P=0.001). In the whole study group (n=20), reperfusion pressures measured at predefined stages in the early reperfusion period showed robust associations with zero flow pressure values measured at the end of the 1-hour MP (immediately after reperfusion: r=0.782, P<0.001; at the 10th minute: r=0.796, P<0.001; and at the 20th minute: r=0.702, P=0.001) and peak creatine kinase MB level (immediately after reperfusion: r=0.653, P=0.002; at the 10th minute: r=0.597, P=0.007; and at the 20th minute: r=0.538, P=0.017). Enzymatic myocardial infarction size was lower in the PCRDS group than in the IS group with peak troponin T (5395±2991 ng/mL versus 8874±1927 ng/mL, P=0.006) and creatine kinase MB (163.6±93.4 IU/L versus 542.2±227.4 IU/L, P<0.001). Conclusions In patients with ST-segment-elevation myocardial infarction, pressure-controlled reperfusion of the culprit vessel by means of gradual reopening of the occluded infarct-related artery (PCRDS) led to better-preserved coronary microvascular integrity and smaller myocardial infarction size, without an increase in procedural complications, compared with IS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02732080.

Keywords: ST‐segment–elevation myocardial infarction; coronary microvascular resistance; intramyocardial hemorrhage; microvascular injury; myocardial edema; primary PCI; reperfusion injury.

Figure 1. Assessment of eligibility, enrollment, randomization, and final groups.

IRA indicates infarct‐related artery; PTCA, percutaneous transluminal coronary angioplasty; and TIMI, thrombosis in my‐ocardial infarction.

Figure 2. Time course of the mean resting (Pd_r) (A) and hyperemic (B) distal pressure (Pd_h) values (mm Hg) recorded distal to the intervention site in the delayed (pressure‐controlled reperfusion with delayed stenting [PCRDS]) and immediate stenting (IS) groups.

In each group, initial measurements were performed immediately after establishing reperfusion. Thereafter, resting pressures were recorded at every 10th minute and hyperemic pressures were recorded at every 20th minute throughout a 1‐hour monitoring period. Mean initial reperfusion pressure was ≈90 mm Hg in the IS and 70 mm Hg in the PCRDS groups (A).

Figure 3. Time course of the arteriolar resistance in relation to changes in stenosis resistance in PCRDS and IS groups.

A, In the delayed stenting group (pressure‐controlled reperfusion with delayed stenting [PCRDS], green lines), complete distal repressurization was established at 30 minutes after reperfusion by the time the arteriolar resistance index (ARI) was close to its highest value, which indicates almost totally recovered autoregulation. In the PCRDS group, mean baseline stenosis resistance (BSR) values were high enough to protect distal microcirculation from the overpressurization after initial balloon angioplasty until the ARI was recovered but low enough not to produce ischemia. B, In the immediate stenting (IS) group (blue lines), reperfusion pressure was completely and abruptly reestablished by stenting at the beginning of the reperfusion by the time ARI value was ≈0, which indicated totally exhausted autoregulation. BSR values became comparable between the 2 arms after stenting was performed in the delayed arm at 30 minutes.

Figure 4. Temporal course of the baseline (resting) microvascular resistance (BMR) and hyperemic microvascular resistance (hMR) values during a 1‐hour monitoring period (MP) after reperfusion.

A, Seven BMR values were measured with 10‐minute intervals beginning from the initial reperfusion until the end of the 1‐hour MP in the delayed (pressure‐controlled reperfusion with delayed stenting [PCRDS]) and immediate stenting (IS) groups. In the IS group, when full‐pressure reperfusion was established by stenting, the BMR value was at its lowest level. However, in the PCRDS group, the BMR value was close to its highest value when stenting was performed at the 30th minute of reperfusion (B) Four hMR values were measured with 20‐minute intervals beginning from initial reperfusion until the end of the 1‐hour MP in the PCRDS and IS groups. A progressive increase in hMR is seen in the IS group.

Figure 5. Temporal course of zero‐flow pressure (Pzf) during a 1‐hour monitoring period (MP) after reperfusion.

A, Four Pzf values were calculated 20 minutes apart beginning from initial reperfusion until the end of the 1‐hour MP in the delayed (pressure‐controlled reperfusion with delayed stenting [PCRDS]) and immediate stenting (IS) groups. In the IS arm, progressively increased Pzf values indicate progressively evolved external compression on microcirculation in this group of patients. (B) Comparison of the mean Pzf values at the end of the 1‐hour MP between the study groups.

Figure 6. The relationship between initial reperfusion pressure (distal intracoronary pressure at the beginning of reperfusion) and zero flow pressure measured at the end of the 1‐hour MP (primary endpoint) and peak CKMB values.

A, Correlations between resting distal intracoronary pressure values (reperfusion pressure) in the early reperfusion period: (1) immediately after reperfusion, (2) at the 10th minute, and (3) at the 20th minute after reperfusion; and zero flow pressure (Pzf) measured at the 60th minute of reperfusion in the study groups. B, Correlations between reperfusion pressure values in the early reperfusion period: (1) immediately after reperfusion, (2) at the 10th minute, and (3) at the 20th minute after reperfusion; and peak creatine kinase MB (CK‐MB) levels.

Figure 7. Coronary microcirculatory response to different myocardial reperfusion strategies: (1) immediate stenting (IS), and (2) pressure‐controlled reperfusion with direct stenting (PCRDS).