The negative inotropic and chronotropic effects of intravenous R during percutaneous transluminal

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1 Br J clin Pharmac 1995; 39: The negative inotropic and chronotropic effects of intravenous R during percutaneous transluminal coronary angioplasty A. J. PIJL1, H. B. VAN WEZEL', J. J. KOOLEN2, J. J. PIEK2, K. KOCH2, A. SWAANI, G. K. DAVID2, C. A. VISSER4 & P. A. VAN ZWIETEN2,3 'Department of Anaesthesiology, 2Department of Cardiology and 3Department of Pharmacotherapy, University of Amsterdam, Amsterdam and 4Department of Cardiology, Free University, Amsterdam, The Netherlands The present study was designed to evaluate the potential anti-ischaemic activity of R in patients with coronary artery disease, scheduled to undergo percutaneous transluminal coronary angioplasty (PTCA). At baseline a complete haemodynamic profile, including cardiac output and coronary sinus blood flow (CSBF) was obtained. In addition, left ventricular pressure and contractility parameters were measured. These parameters were also measured before and after additional balloon inflations, preceded by placebo and R i.v. R was infused intravenously at three different dosages, namely: 20 mg (n = 8), 30 mg (n = 2), 40 mg (n = 2). No significant differences were observed between placebo and R (20 mg) concerning time to onset and duration of ST-segment changes and symptomatic angina pectoris, respectively. The other parameters did not show differences compared with the baseline values when R (20 and 30 mg) was infused. However, the two patients receiving a dose of 40 mg R developed a dramatic decrease in systolic and diastolic blood pressure, left ventricular (LV) systolic pressure, peak positive dp/dt and the CSBF (ranging from 30-50%), while the LV end-diastolic pressure increased by 100%. The two patients who received this dose became pale and cyanotic and did not respond to verbal commands. In summary, no anti-ischaemic effects of R were observed under these conditions, whereas at the highest dose (40 mg) R induced hypotension and a reduction in cardiac contractile force. Keywords R myocardial ischaemia PTCA contractility Introduction The compound R (Janssen Pharmaceuticals, Beerse, Belgium) is the prototype of a new class of anti-ischaemic substances. R (N-[l-[4-(4-fluorophenoxy)-butyl] -4-piperidinyl)-N-methyl-2-benzothiazolamine), is assumed to interfere with the fast Na+ channel, at the level of the myocardial cell membrane, in particular under pathological (ischaemic) conditions and this mechanism is regarded as a novel cardioprotective measure [1, 2]. In animal models it has been shown that this compound has cardioprotective, anti-ischaemic and antiarrhythmogenic properties. There is no evidence of myocardial depression or vasodilatation [3-5]. In open studies in healthy volunteers, the i.v. administration of R up to 35 mg was well-tolerated, apart from gastrointestinal complaints, tiredness and dizziness. No depressant effects on the cardiovascular system or adverse events have been reported so far [6, 7]. The percutaneous transluminal coronary angioplasty (PTCA) procedure offers the opportunity to study acute myocardial ischaemia under controlled Correspondence: Dr A. J. Pijl, Academic Medical Centre, Department of Anaesthesiology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands 1995 Blackwell Science Ltd 531

2 532 A. J. Pijl et al. and reproducible conditions. It was the aim of the present study to evaluate the effects of R on ischaemia, haemodynamics, coronary dynamics, myocardial metabolism and contractility in patients undergoing PTCA. Methods Patient characteristics Eight male and four female patients scheduled for elective PTCA gave informed consent to participate in this study, which had the approval of the local medical ethics committee. The patients had to meet the following inclusion criteria: coronary artery stenosis of the proximal left anterior descending artery, proximal dominant right coronary artery or large left circumflex artery, documented by a coronary angiogram showing significant stenosis (2 70%) and the absence of collateral vessels of the heart. Cardiac catheterization All chronic oral medication was continued until the morning of cardiac catheterization. In the catheterization laboratory left heart catheterization was performed via the percutaneous femoral approach. An 8Fr guiding catheter (Schneider-Shiley-Europe, Biilach, Switzerland) was used for guidance of the balloon catheter and inserted via the right femoral artery. The aortic pressure was measured at the tip of the guiding catheter. A micromanometer-tipped catheter (Millar Instruments Inc., Houston, Texas, USA) was inserted via the left femoral artery into the left ventricle for recording of haemodynamic parameters (including dp/dt), using a commercially available software package (Crystal Biotech, Holliston, USA). A flow directed balloon-tipped pulmonary artery catheter (Baxter/American Edwards Laboratories, Santa Ana, USA) was inserted via the right femoral vein. Cardiac output was measured by the single bolus thermodilution method. A coronary sinus thermodilution catheter (Wilton- Webster Laboratories, Altadena, California, USA, type CCS-7U-90B) was introduced via the left subclavian vein. Blood samples were taken simultaneously from the femoral artery and coronary sinus for the determination of the 02-saturation and PO2. A 12-lead electrocardiogram (ECG) was recorded throughout the whole procedure (paper speed: 25 mm S-l). Trial medication and administration The trial medication was supplied in 4 ml glass ampoules containing either placebo (mannitol, tartaric acid, sodium hydroxide, ph: 2.9) or R (mannitol, tartaric acid, R mg ml-', ph: 2.8). Prior to use, the trial medication (placebo and R 56865) was diluted to 10 ml with glucose 5%, which was then injected intravenously over 3 min via the proximal lumen of the pulmonary artery catheter. Experimental protocol Statistical analysis Statistical significance was evaluated using the Wilcoxon signed rank test. The level of significance was considered to be P < Results The patients were comparable with respect to age, weight, height, degree of coronary artery disease and cardiovascular medication. The first eight patients received 20 mg R 56865, two subsequent patients placebo rest A rest B first inflation R rest C second inflation rest D rest E Instrumentation and initial therapeutic dilatation(s) -5 Figure 1 V 11 III IV Time (min) Before starting the actual study protocol, the patients were first treated with coronary angioplasty involving single or multiple balloon inflations as required. The number of therapeutic coronary dilatations could not be standardized for ethical reasons. The duration of balloon inflations was set at 60 s. The inflation pressure ranged from 4-8 atmosphere. A complete haemodynamic profile including thermodilution cardiac output (CO) was obtained at baseline. In addition left ventricular end diastolic pressure (LVEDP), peak positive peak dp/dt (LVdP/dt+), coronary sinus blood flow (CSBF), arterial and coronary sinus 02 blood gas samples were obtained. This was done at fixed intervals (see Figure 1). Calculated haemodynamic data and myocardial metabolic parameters were calculated according to standard equations. V VI VIl ---40bo Experimental protocol (flow chart). The study periods are indicated by Roman numerals Blackwell Science Ltd, British Journal of Clinical Pharmacology, 39,

3 Short report 533 Table 1 Haemodynamic measurements and calculations (means ± s.e. mean). Shown are the heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), left ventricular end-diastolic pressure (LVEDP), positive left ventricular peak dp/dt (LVdP/dt+), coronary sinus blood flow (CSBF), and the cardiac index (CI) at three different dosages of R The study periods are explained in Methods. R was infused after period IV Study period Parameter Dosage I II III IV V VI VII HR (beats min-') 20 mg 68 ± 3 68 ± 2 65 ± 3 68 ± 3 69 ± 2 68 ± 2 66 ± 2 30mg 61±8 63±8 63±11 61 ± 6 63±6 61±9 61±7 40mg 61±1 61 ± 1 64±0.0 61±1 62±1 58±3 56±3 SBP(mmHg) 20mg 144±7 145±7 140±5 142 ± 6 140±6 141±5 143±7 30mg 138± ±6 134± ± 6 128± 1 144± ± 10 40mg 146 ± 4 141±6 148±10 139±6 103 ± 5 102±5 102±5 DBP(mmHg) 20mg 83±4 83±4 83±3 81±3 81±3 84±4 81±3 30mg 80±3 83±4 86±7 79±4 80±7 86±9 80±7 40mg 93± 6 91 ± 6 91 ± 8 88± 6 50± 7 52± 9 50± 7 LVEDP(mmHg) 20mg 9 ± 2 8±1 11±1 9±1 8 ±1 10±2 9±1 30mg 10± 1 12± 1 13±4 11 ± 1 14±2 16± 1 18± 1 40mg 8±0.0 12± ± 1 10±0.4 14±0.0 16±0.4 16± 1 LVdP/dt(+) (mm Hg) 20 mg 2240± ± ± ± ± ± ± mg 2879±5 3297± ±3 3120± ± ± ± mg 2239 ± ± ± ± ± ± ± 5 CSBF (ml min-1) 20 mg 119 ± ± ± ± ± ± ± 15 30mg 102± ±2 132 ± ± 13 96± ± 15 98±7 40mg 127±7 104±5 117±8 118±8 112± 12 95±6 92± 1 CI ( min'm-2) 20 mg 3 ± ± ± ± ± ± ± mg 4±0.2 3±0.0 2±0.4 2± 1 3±0.1 2± 0.0 3±0.2 40mg 4±0.0 4±0.4 4±0.2 4±0.2 4± 1 3±0.2 3±0.0 received 30 mg, and the last two patients received 40 mg R ST-segment changes and angina pectoris The time to onset of ST-segment changes (> 1 mm) on the electrocardiogram and/or angina pectoris was not different during the first balloon inflation (following placebo administration), compared with the second one (following administration of R , 30 or 40 mg). The total duration of ST-segment changes and angina pectoris was not different during the first or second balloon inflations. The degree of ST-segment changes did not show any differences between placebo and R at different dosages. Measured and calculated parameters (Table 1) Compared with baseline values (measurement point I) there were no changes at any of the subsequent measurement points in parameters in the patients treated with 20 and 30 mg R However, the two patients who received 40 mg R (following measuring point IV) developed a different haemodynamic pattern. At measurement points V, VI and VII there was a dramatic decrease in heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), LVdP/dt(+), and CI. We also observed a substantial increase in LVEDP. Adverse reactions The two patients receiving a dose of R mg, developed cardiovascular collapse, nausea and pallor, immediately following the second trial inflation; moreover they did not respond to simple questions and commands. To exclude vagal overstimulation atropine 0.5 mg was given, but with no effect. The nausea and pallor subsided within 30 min, whereas the decrease in blood pressure persisted for a few hours. Both patients recovered completely over 12 h. At lower doses, no patients experienced adverse reactions. Due to the adverse events in the patients receiving R mg, it was decided to discontinue the study. Discussion Ischaemia during coronary interventional procedures may offer serious problems. Pharmacological attempts to reduce ischaemia during PTCA have been carried out with the usual types of anti-ischaemic drugs, such as i.v. administered calcium antagonists diltiazem [8] and nicardipine [9]. The aforementioned drugs have been proven to reduce myocardial ischaemia during PTCA. The attenuation of ischaemia is achieved by an increase in coronary blood flow (i.e. myocardial 02 supply), a decrease in myocardial contractility and/or workload and thereby a decrease in myocardial oxygen demand. At present there exists great interest for compounds which possess anti-ischaemic properties with minimal depressant effects on cardiac contractility. Theoretically, R may be such a compound. Under pathological conditions there occurs a dysfunction of fast Na+ channels, causing an excessive entry 1995 Blackwell Science Ltd, British Journal of Clinical Pharmacology, 39,

4 534 A. J. Pijl et al. of Na+, followed by intracellular Ca2+ overload via a passive Na+/Ca2+ exchange. R prevents an intracellular Na+ overload by blocking the Na+ channels (only under pathological, i.e. ischaemic conditions) and thereby it prevents a secondary Ca2+ overload in the cell, which is known to be the final pathway leading to cell death [1, 2, 10, 11]. This anti-ischaemic effect of R has been evaluated and proven in different species. In a comparative study in rat isolated hearts we found a clear anti-ischaemic effect of R at a perfusate concentration which caused considerably less reduction in LVP and dp/dt than the calcium antagonist nifedipine [12]. Our results were in keeping with in vivo and in vitro data reported by others [3-5]. In healthy volunteers [6, 7] R at 5, 20 and 35 mg i.v. proved well-tolerated without causing change in haemodynamic parameters. However, in the present study the use of R i.v. did not produce any detectable anti-ischaemic effects. In addition, considerable side effects occurred in the two patients treated with R mg i.v. Although CO was well-maintained, we found negative inotropic activity as reflected by a reduction in peak positive dp/dt. It is difficult to explain the unexpected adverse events observed in our two patients, receiving 40 mg R i.v. Nausea, dizziness and visual disturbances suggest the involvement of the central nervous system (CNS). It is well known that lipophilic compounds readily cross the blood-brain barrier. R is indeed a highly lipophilic agent. Both myocardial contractility and conduction were suppressed, as reflected by reduction in peak positive dp/dt, arterial blood pressure and bradycardia. These haemodynamic abnormalities started immediately after the second trial inflation and persisted in the following 8 h. It may be that a too strong blockade of the sodium inward current caused abnormal electrophysiological conditions resulting in inadequate action potential patterns and depolarisation at the level of the myocardial cell membrane. This may have resulted in depressed contractility of the myocardium. A similar mechanism may have influenced the SA node. Possible explanations for the absence of detectable anti-ischaemic effects of R in our clinical study include: 1) The experimental set-up may be unsuitable for the demonstration of the anti-ischaemic effects of R PTCA is a model of 'supply ischaemia' whereas 'high demand ischaemia' as a result of pacing and/or increased contractility could have had a different effect. 2) A potential source of error is the lack of a separate placebo group of patients. Theoretically, the use of repeated bouts of ischaemia induced by intracoronary balloon inflation may have caused a summation of post-ischaemic stunning although we could not find evidence to support this theory [13]. On the contrary, this may have resulted in a 'training effect', i.e. preconditioning, attenuating the effect of the last balloon inflation following R i.v. Less subjective anginal discomfort and less ST-segment shift was observed by Deutsch et al. during the second balloon occlusion when compared with the initial occlusion in patients undergoing PTCA [14]. 3) It is conceivable that the relatively high infusion rate resulted in exceptionally high plasma concentrations (R was infused over 3 min). 4) The route of administration may have been unsuitable to demonstrate anti-ischaemic properties of R in man. Intracoronary injection of R at low dosages may have been more effective than the intravenous route, owing to a higher local concentration of the drug, without its systemic haemodynamic effects and neurological adverse events. Pretreatment for several days with R given orally would probably have been a preferable route of administration. Accordingly, a steady state would then have been achieved, which was probably not obtained after the acute administration of the drug as in our experiments. In conclusion, the results of our study suggest that the intravenous administration of R (20 and 30 mg), in patients undergoing PTCA, is not associated with any detectable anti-ischaemic or haemodynamic effects. R mg was equally ineffective in producing anti-ischaemic effects and this dose resulted in considerable haemodynamic and neurological adverse events, which are likely to involve the CNS. This study has once more demonstrated, that there may exist a strong discrepancy between animal experiments and human studies. References 1 Koch P, Wilffert B, Peters T. R 56865: A new antiischemic principle. Cardiovasc Drug Rev 1990; 3: Ver Donck L, Borgers M. Myocardial protection by R 56865: a new principle based on prevention of ion channel pathology. Am J Physiol 1991; 261: H1828-H Vandeplassche G, Thone F, Borgers M. Protective effects of R against ischemic damage in the isolated rabbit heart. Eur J Pharmac 1991; 202: Gamer JA, Hearse DJ, Bernier M. R 56865, a potent new antiarrhythmic agent, effective during ischemia and reperfusion in the rat heart. J cardiovasc Pharmac 1990; 16: Vandeplassche G, Hermans C, Wouters L, Borgers M. Effects of R 56865, a preventer of cellular calcium overload, on left ventricular diastolic properties during pacing-induced ischemia in dogs. J cardiovasc Pharmac 1991; 17: Lucker PW. 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