ESC Congress 2003: Sudden cardiac death - New drug therapies improve outcome

Sudden cardiac death is mostly due to coronary artery disease, and it is one of the major â€žkillers" in our industrialized world.

If someone who is suffering from sudden cardiac death is very lucky, he or she may be resuscitated by bystanders or professionals with chest compressions and ventilation (in case of bystanders with moth-to-mouth or mouth-to-nose ventilation).

Nevertheless and still, only one out of ten patients suffering from out-of-hospital sudden cardiac death (cardiac arrest) can be resuscitated successfully and survives without any neurological damage. Therefore, the prognosis of patients suffering from out-of-hospital cardiac arrest is generally very poor.
Unfortunately, no specific treatment options which can be used during CPR to improve outcome are available at present.

Now, at the Department of Anesthesiology, University of Heidelberg, Germany, a new therapy has been developed that can markedly improve (i.e., double) the survival rate after sudden cardiac death. Professor Bernd Böttiger and his colleagues from that Department observed, that following cardiac arrest, there is a disseminated coagulation activation and blood clotting in all vessels of the body. If these blood clots (thrombosis) are resolved with specific drugs (thrombolytic agents), far more sudden cardiac death victims than before can be reanimated. This success has agined worldwide attention in the scientific community recently.

Background basic science

Interestingly, in about 50% to more than 70% of patients who had to be resuscitated after out-of-hospital cardiac arrest, either acute myocardial infarction or massive pulmonary embolism and, thus, intravascular blood clots (i.e., thrombosis) caused the cardiocirculatory arrest.

Although cardiac arrest initiated by intracoronary thrombosis in the case of myocardial infarction is quite different from pulmonary embolism, thrombolysis (i.e., lysis of these blood clots with specific drugs that can be administered to the patients) is an effective and causal treatment strategy for both of these disease entities.

Unfortunately, however, thrombolytic therapy during cardiopulmonary resuscitation (CPR), however, has traditionally been contraindicated due to the fear of severe bleeding complications associated with CPR procedures.

Recent clinical case reports and small case series now have suggested that thrombolysis during CPR can contribute to hemodynamic stabilization and long-term survival in patients suffering cardiac arrest following acute myocardial infarction and massive pulmonary embolism. Moreover, an unusual proportion of patients in these reports survived prolonged periods of cardiac arrest and CPR without any or only minor neurological deficits. This is due to the fact that, after cardiac arrest, reperfusion is associated with a marked and disseminated intravascular activation of blood coagulation without adequate activation of endogenous fibrinolysis and, thus, with intravascular clotting and fibrin formation. Therefore, besides representing a causal therapeutic approach in acute myocardial infarction and pulmonary embolism, thrombolysis during CPR may bring about a general improvement in microcirculatory flow throughout the entire organism, including cerebral reperfusion.

In fact, experimental data from our group and from others indicate that thrombolysis during CPR improves early microcirculatory reperfusion in the brain and there is a positive effect of one specific thrombolytic agents, tissue-type plasminogen activator (rt-PA), on cerebral tolerance to ischemia.

Experimental and clinical studies have revealed that cardiocirculatory arrest and CPR are associated with a marked activation of blood coagulation without adequate activation of endogenous fibrinolysis. Therefore, intravascular blood coagulation, fibrin formation and subsequent blood clotting with microthromboses are distributed throughout the entire microcirculation after cardiac arrest.

Consistent with this pathophysiological finding, the administration of heparin and/or thrombolytic agents is associated with an immediate improvement in cerebral microcirculatory reperfusion, an improvement in myocardial contractility, and an increase in the survival rate after experimentally induced cardiac arrest. It appears that thrombolysis may act very quickly in these disastrous situations.
Recent clinical studies

Under these circumstances, we performed a prospective clinical trial to evaluate the concept of thrombolysis during CPR. In this study, patients undergoing CPR after out-of-hospital cardiac arrest of cardiac etiology in whom return of spontaneous circulation (ROSC) was not achieved within 15 min were studied prospectively.

According to the Utstein criteria, outcome was assessed for a 1-year period (control group). In the time period immediately thereafter, patients were treated with a bolus of 5000 U of heparin and 50 mg over 2 min of tissue-type plasminogen activator (rt-PA) at 15 min of unsuccessful CPR. This intervention was repeated if ROSC was not achieved within 30 min.

Overall, 90 patients were included; heparin and rt-PA were given in 40 patients. There were no bleeding complications related to the CPR procedures. In the rt-PA group, ROSC was achieved in 68%, and 58% of patients were able to be admitted to a cardiac intensive care unit, as compared with 44% (p=0.026) and 30% (p=0.009) of controls, respectively. At 24 h after cardiac arrest 35% of rt-PA treated patients (versus 22% of controls; p=0.171) were still alive, and 15% of rt-PA treated patients (versus 8% of controls) were discharged alive from the hospital.

Therefore, the survival rate was nearly doubled, when thrombolytic agents were given to the patients with sudden cardiac death. This is a very remarkable finding, which was confirmed by two other retrospective studies from the Department of Anesthesiology (Univ. of Innsbruck) in Innsbruck and from the Department of Emergency Medicine (Univ. of Vienna) in Vienna recently.

Fig. Results of the prospective clinical study in patients undergoing CPR after out-of-hospital cardiac arrest of cardiac etiology in whom return of spontaneous circulation (ROSC) was not achieved within 15 min. According to the Utstein criteria, outcome was assessed for a 1-year period (control group). In the time period immediately thereafter, patients were treated with a bolus of 5000 U of heparin and 50 mg over 2 min of tissue-type plasminogen activator (rt-PA) at 15 min of unsuccessful CPR. This intervention was repeated if ROSC was not achieved within 30 min.
Overall, 90 patients were included; heparin and rt-PA were given in 40 patients. There were no bleeding complications related to the CPR procedures. In the rt-PA group, ROSC was achieved in 68%, and 58% of patients were able to be admitted to a cardiac intensive care unit, as compared with 44% (p=0.026) and 30% (p=0.009) of controls, respectively. At 24 h after cardiac arrest 35% of rt-PA treated patients (versus 22% of controls; p=0.171) were still alive, and 15% of rt-PA treated patients (versus 8% of controls) were discharged alive from the hospital (see, Böttiger BW, Bode C, Kern S, Gries A, Gust R, Gl'�tzer R, Bauer H, Motsch J, Martin E (2001) Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial. Lancet 357:1583-1585).

Professor Bernd Böttiger and his colleagues conclude from these data that following initially unsuccessful out-of-hospital CPR, thrombolytic therapy combined with heparin is safe, and it appears to improve patient outcome.

Therefore, there is a new therapeutic option available, that can be used to improve patients outcome. Since data from large scale clinical multicentre trials are still lacking, the decision to treat a patient must be performed on an individual basis at the moment.

Future European multicentre trail

Before this treatment strategy can be recommended generally for all patients suffering from sudden cardiac death, a randomized controlled clinical outcome trial focusing on that therapeutic concept must be performed. This is ethical and necessary now. If the concept of thrombolysis during CPR is associated with an improved outcome in such a large scale trial, this would change the acute prognosis of thousands of patients.

It is well known that up to 90 out of 100.000 inhabitants annually were resuscitated following out-of-hospital cardiac arrest. That means that such a new treatment option may be indicated in up to to 270.000 patients annually in the European Community (and, in addition, far more than this in the US and in the rest of the world).

Professor Bernd Böttiger, his group and colleague from different European countries are currently preparing a European randomized and controlled multicentre trial that will enrol about 1000 patients, to finally confirm that very promising new therapy. This study will be conducted under the aegis of the European Resuscitation Council and in cooperation with Boehringer Ingelheim.

Bernd W. Böttiger, M.D., D.E.A.A
University of Heidelberg, Heidelberg
Germany

European Society of Cardiology (ESC)

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ESC Congress 2003: Sudden cardiac death - New drug therapies improve outcome

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