Thiele H, Akin I, Sandri M, Fuernau G, De Waha S, Meyer-Saraei R, et al. PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock. N Engl J Med. 2017 Dec 21;377(25):2419–32.
Introduction
Cardiogenic shock following acute myocardial infarction carries high mortality; besides, long-term outcomes remain poor among survivors (1). The SHOCK trial, the first systematic study that evaluated the efficacy of emergency revascularization in patients with cardiogenic shock, was published nearly a quarter of a century ago. In a randomized controlled trial (RCT), emergency revascularization by angioplasty or coronary artery bypass grafting within 36 hours after acute myocardial infarction was compared with initial medical stabilization. Mortality at 6 months was significantly lower among patients who underwent emergency revascularization (50.3% vs. 63.1%) (2). In a follow-up study, long-term outcomes were evaluated over 1–11 years (3). Early revascularization was associated with a 67% improvement in the 6-year survival compared with initial medical stabilization. The survival benefit of early revascularization persisted through the entire follow-up period of up to 11 years.
Apart from the culprit vessel lesion, cardiogenic shock following acute myocardial infarction is often associated with chronic occlusion of other vessels (4). Besides, the presence of multivessel disease is associated with higher mortality compared to single-vessel disease (5,6). In this scenario, should revascularization be confined to the infarct-related vessel alone or include other vessels with clinically important stenoses? Emergency revascularization of all affected vessels may potentially enhance overall myocardial perfusion and augment cardiac function. However, a multivessel revascularization strategy could be hazardous too – it may lead to worsening of ischemia, volume overload, and renal dysfunction related to a higher dose of contrast administration.
In the SHOCK trial, percutaneous coronary intervention (PCI) of the culprit lesion alone was the most common initial intervention. Intuitively, more complete revascularization might be expected to offer additional benefit; however, the subgroup of patients who underwent initial multivessel PCI revealed higher mortality compared to the subgroup that underwent revascularization of the culprit lesion alone (2).
A meta-analysis including 10 cohort studies compared immediate multivessel intervention with revascularization of the culprit lesion alone in patients with cardiogenic shock following acute myocardial infarction. Most patients (80.3%) underwent revascularization of the culprit lesion alone. The short-term mortality was significantly lower in those who underwent revascularization of the culprit lesion alone (28.8% vs. 37.5%). The long-term mortality, reinfarction rates, new-onset stroke, and acute renal failure did not differ significantly between the two groups.
The DANAMI-3 —PRIMULTI trial studied patients with ST-elevation myocardial infarction (STEMI) who had additional, clinically significant coronary stenosis in vessels other than the infarct-related artery (7). Patients were randomly allocated to undergo primary percutaneous coronary intervention of the infarct-related artery alone, or to complete revascularization guided by the fractional flow reserve. The composite primary outcome, including all-cause mortality, non-fatal myocardial infarction, and later revascularization of lesions in non-infarct-related arteries, was significantly lower with complete revascularization. However, this study had excluded patients with cardiogenic shock.
Considering the lack of firm evidence, there were no strong recommendations from guidelines. While the European guidelines recommended consideration of PCI to non-culprit lesions in the presence of cardiogenic shock (8), the US guidelines suggested revascularization of non-culprit vessels if cardiogenic shock persisted (9). Against the background of clinical equipoise, the CULPRIT-SHOCK trial was conceived (10). The investigators hypothesized that PCI of the culprit lesion alone, with revascularization of concurrent lesions at a later stage as appropriate, would lead to more favorable clinical outcomes compared with immediate, multivessel PCI in patients with cardiogenic shock following acute myocardial infarction.
Population and design
The CULPRIT-SHOCK trial was conducted between April 2013 to April 2017 and included 706 patients from 83 centers across Europe. Patients with acute myocardial infarction (ST-segment elevation or non-ST-segment elevation) complicated by cardiogenic shock, with an identified culprit lesion were eligible. Patients had multivessel disease, defined as involving at least two major vessels with more than 70% stenosis. Cardiogenic shock was defined as a systolic BP of <90 mm Hg for >30 minutes or the requirement for catecholamine support to maintain systolic BP >90 mm Hg, with clinical signs of pulmonary congestion and diminished organ perfusion including one the following: altered sensorium, cold and clammy extremities, urine output of <30 ml/hour, and arterial lactate level of >2.0 mmol/L.
Excluded
Patients who had undergone cardiopulmonary resuscitation for >30 min, those with no intrinsic myocardial activity, fixed dilated pupils, indication for primary coronary artery bypass grafting, cardiogenic shock due to a mechanical cause, duration of shock >12 hours, massive pulmonary embolism, pre-existing severe renal dysfunction, age >90 years, and comorbidities with a life expectancy of <6 months were excluded.
Randomization
Immediately following angiography, patients were randomized, in a 1:1 ratio to PCI of the culprit lesion alone or immediate multivessel PCI.
PCI of the culprit lesion alone
Following randomization, PCI was performed on the culprit lesion alone. Staged revascularization of non-culprit lesions was carried out later, as deemed clinically appropriate. The requirement for later revascularization was based on the presence of residual ischemic lesions and the overall clinical and neurological status. Residual ischemia was assessed by measurement of the fractional flow reserve (FFR). FFR is defined as the ratio of the maximum achievable flow through a stenotic segment to the maximum achievable flow with the hypothetical absence of blockage.
FFR = Pressure distal to the blockage / pressure proximal to the blockage. The normal FFR is 1.0. A low FFR indicates reduced flow; e.g., an FFR of 0.70 indicates a maximum flow through a blocked artery of 70% of the flow achievable had there been no blockage (11).
Multivessel PCI
In the multivessel group, PCI of the culprit lesion was performed first, followed by PCI of all major coronary arteries with >70% stenosis. All chronic total occlusions were meant to be recanalized during the acute phase. The maximum dose of contrast material recommended was 300 ml.
Common management
Other therapeutic interventions were carried out as clinically appropriate, including mechanical circulatory support and renal replacement therapy, based on accepted ICU guidelines. Renal replacement therapy was considered in the presence of intractable volume overload, a potassium level of >6.0 mmol/L, blood urea level of >50 mg/dl, or persistent metabolic acidosis with a pH of <7.2.
Sample size calculation
The sample size was calculated based on the event rate of the composite primary outcome – the all-cause mortality and severe acute kidney injury requiring renal replacement therapy at 30 days post-randomization. The investigators assumed an event rate of 50% in the multivessel group and 38% in the culprit-lesion-only group. A sample size of 684 patients provided the trial with 80% power to disprove the null hypothesis at a two-sided alpha level of 0.048. Seven hundred-and six patients were recruited, allowing for a withdrawal rate of 3%.
Results
Among the 706 patients included, 351 were assigned to culprit-lesion-only PCI and 355 to multivessel PCI. In the final analysis, there were 344 patients in the culprit-lesion-only group and 341 patients in the multivessel PCI group. Crossover occurred both ways; culprit-lesion-only to multivessel in 43 patients (12.5%) and contrariwise in 32 patients (9.4%). Staged revascularization of concurrent, non-culprit lesions was performed in 17.7% of patients in the culprit-lesion-only group. As expected, the total contrast dose was significantly higher in the multivessel group. Mechanical circulatory support and adjunctive medications were used at similar rates in both groups.
The primary outcome
The primary outcome, a composite of all-cause mortality and severe acute kidney injury requiring renal replacement therapy at 30 days post-randomization, was significantly lower in the culprit-lesion-only group compared with the multivessel group [45.9% vs. 55.4%; relative risk: 0.83 (0.71–0.96); P = 0.01)]. Per-protocol analysis revealed similar outcomes, favoring the culprit-lesion-only strategy. The composite primary outcome was similar in predefined subgroups of patients based on age, gender, presence of diabetes, hypertension, type of infarct (STEMI vs. NSETMI), location of infarct, previous infarct, the number of affected vessels, and the presence of chronic total occlusion.
Secondary outcomes
The secondary outcomes included individual components of the composite primary outcome. The 30-day all-cause mortality was significantly lower with a culprit-lesion-only strategy compared to multivessel intervention [43.3% vs. 51.6%; relative risk, 0.84; (0.72 –0.98); P = 0.03]. The requirement for renal replacement therapy did not differ significantly between the two groups. The incidence of recurrent myocardial infarction, stroke, rehospitalization for cardiac failure, and bleeding complications were similar in both groups. Among other secondary outcomes, the median time to attain hemodynamic stability (2 days in both groups), duration of catecholamine support (2 days in both groups), duration of ICU stay (5 days in both groups), and the duration of mechanical ventilation (3 days in both groups) were also similar in both groups.
Why did multivessel PCI lead to worse outcomes?
The authors hypothesized that the higher 30-day mortality may have occurred due to the higher mean dose of contrast used in the multivessel PCI group (250 ml vs. 190 ml), leading to a more profound decline in renal function. However, the requirement for renal replacement therapy was not significantly different between the two groups. Acute left ventricular volume overload may also have arisen from the increased dose of contrast, adversely impacting myocardial function and recovery. The longer procedural time associated with multivessel intervention may also have jeopardized outcomes in an unstable clinical situation, through increased bleeding and inflammation. Furthermore, attempting PCI in stable lesions may have provoked further damage to the already compromised myocardium (12).
Strengths
The CULPRIT-SHOCK trial was a well-conducted RCT, with the sole participant being lost to follow-up. Risk estimates for the primary endpoint were consistent on per-protocol, intention-to-treat, and as-treated analysis, adding to the robustness of the findings. The study findings challenged conventional wisdom and the limited antecedent evidence that suggested improved clinical outcomes with a more complete revascularization strategy.
Weaknesses
Blinding of the treatment strategy was technically not feasible, and hence, may have led to bias, especially in the assessment of secondary outcomes. The management of cardiogenic shock revolves around many complex interventions; it is plausible that some bias may have occurred during the conduct of the study due to the lack of blinding. Due to the absence of a final informed consent, some patients could not be included in the final analysis. Crossover occurred from the culprit-lesion-only to the multivessel strategy arm in 43 patients (12.5%) and contrariwise in 32 patients (9.4%). Crossovers underline the importance of individualization of care and clinical judgment in the setting of multivessel involvement. The study protocol mandated revascularization of chronic total occlusions; would such a strategy have contributed to adverse outcomes in the multivessel strategy group? Considering a substantial number of patients who underwent cardiopulmonary resuscitation, before PCI (54%), evaluation of the neurological status may have been relevant.
One-year outcomes
Although immediate multivessel PCI, including non-culprit lesions may be associated with adverse outcomes at 30 days, how does it impact long-term outcomes? A follow-up of the CUPRIT-SHOCK subjects evaluated clinical outcomes at 1 year (13). Data of all patients who had at least 30 days of follow-up were included; analysis was based on intention-to-treat. All except one patient were followed up between 30 days to 1 year. The overall mortality between 30 days and 1 year was 6.6%. Although the all-cause mortality remained higher in the multivessel PCI group at 1 year, the difference was no longer statistically significant [50.0% vs. 56.9%; relative risk, 0.88; (0.76 –1.01)]. Death due to cardiovascular causes was also not significantly different between the two groups at the 1-year follow-up. At the end of 1 year, repeat procedures for revascularization was performed more often in the culprit-lesion-only group (32.3% vs. 9.4%). The rehospitalization rate for congestive cardiac failure was low in both groups, although it was significantly higher with the culprit-lesion-only strategy (5.2% vs. 1.2%).
This follow-up study did not support the hypothesis that a multivessel revascularization strategy may improve longer term outcomes among patients presenting with cardiogenic shock.
Summary
The CULPRIT-SHOCK trial addressed an important clinical question with contrasting evidence and viewpoints. The study evaluated a culprit-vessel-only compared with a multivessel PCI strategy among patients with cardiogenic shock following acute myocardial infarction. PCI of the culprit lesion alone led to a lower 30-day all-cause mortality and the requirement for renal replacement therapy compared to a multivessel strategy. The favorable primary outcome was driven almost entirely by improved 30-day survival in the culprit-lesion-only group; the need for renal replacement therapy was similar in both groups. This well-conducted RCT with near complete follow-up offered convincing evidence that it may be more appropriate to direct intervention to the culprit lesion alone in patients with acute myocardial infarction complicated by cardiogenic shock. It is important to emphasize the patient population included were severely ill – 81% underwent mechanical ventilation, 90% required catecholamine support, and 54% had undergone cardiopulmonary resuscitation prior to PCI. Hence, the findings of the study may not be extrapolatable to those who are less severely ill. Besides, as the authors pointed out, one size may not fit all and the type of intervention requires adaptation to the clinical setting.
References
1. Hochman JS, Sleeper LA, White HD, Dzavik V, Wong SC, Menon V, et al. One-year survival following early revascularization for cardiogenic shock. JAMA. 2001 Jan 10;285(2):190–2.
2. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, et al. Early Revascularization in Acute Myocardial Infarction Complicated by Cardiogenic Shock. N Engl J Med. 1999 Aug 26;341(9):625–34.
3. Hochman JS, Sleeper LA, Webb JG, Dzavik V, Buller CE, Aylward P. Early Revascularization Improves Long-Term Survival for Cardiogenic Shock Complicating Acute Myocardial Infarction. 2007;
4. Conde-Vela C, Moreno R, Hernández R, Pérez-Vizcayno MJ, Alfonso F, Escaned J, et al. Cardiogenic shock at admission in patients with multivessel disease and acute myocardial infarction treated with percutaneous coronary intervention: Related factors. Int J Cardiol. 2007 Dec 15;123(1):29–33.
5. Webb JG, Lowe AM, Sanborn TA, White HD, Sleeper LA, Carere RG, et al. Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial. J Am Coll Cardiol. 2003 Oct 15;42(8):1380–6.
6. Sanborn TA, Sleeper LA, Webb JG, French JK, Bergman G, Parikh M, et al. Correlates of one-year survival inpatients with cardiogenic shock complicating acute myocardial infarction: angiographic findings from the SHOCK trial. J Am Coll Cardiol. 2003 Oct 15;42(8):1373–9.
7. Engstrøm T, Kelbæk H, Helqvist S, Høfsten DE, Kløvgaard L, Holmvang L, et al. Complete revascularisation versus treatment of the culprit lesion only in patients with ST-segment elevation myocardial infarction and multivessel disease (DANAMI-3—PRIMULTI): an open-label, randomised controlled trial. Lancet Lond Engl. 2015 Aug 15;386(9994):665–71.
8. Ibánez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Rev Espanola Cardiol Engl Ed. 2017 Dec;70(12):1082.
9. Patel MR, Calhoon JH, Dehmer GJ, Grantham JA, Maddox TM, Maron DJ, et al. ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2016 Appropriate Use Criteria for Coronary Revascularization in Patients With Acute Coronary Syndromes : A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Association for Thoracic Surgery, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and the Society of Thoracic Surgeons. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol. 2017 Apr;24(2):439–63.
10. Thiele H, Akin I, Sandri M, Fuernau G, De Waha S, Meyer-Saraei R, et al. PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock. N Engl J Med. 2017 Dec 21;377(25):2419–32.
11. Pijls NH, De Bruyne B, Peels K, Van Der Voort PH, Bonnier HJ, Bartunek J Koolen JJ, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med. 1996 Jun 27;334(26):1703–8.
12. Thiele H, Desch S. CULPRIT-SHOCK (Culprit Lesion Only PCI Versus Multivessel Percutaneous Coronary Intervention in Cardiogenic Shock): Implications on Guideline Recommendations. Circulation. 2018 Mar 27;137(13):1314–6.
13. Thiele H, Akin I, Sandri M, De Waha-Thiele S, Meyer-Saraei R, Fuernau G, et al. One-Year Outcomes after PCI Strategies in Cardiogenic Shock. N Engl J Med. 2018 Nov;379(18):1699–710.
Best critical care blogs of 2023: https://blog.feedspot.com/critical_care_blogs/
