Chronobiology and chronotherapy of ischemic heart disease

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Advanced Drug Delivery Reviews 59 (2007) 952 – 965 www.elsevier.com/locate/addr

Chronobiology and chronotherapy of ischemic heart disease ☆ Francesco Portaluppi a,⁎, Björn Lemmer b a

Hypertension Center, Department of Clinical and Experimental Medicine, University of Ferrara, via Savonarola 9, I-44100 Ferrara, Italy b Institute of Pharmacology and Toxicology, University of Heidelberg, Maybachstrasse 14, D-68169 Mannheim, Germany Received 28 May 2006; accepted 7 July 2006 Available online 5 July 2007

Abstract The occurrence of the clinical manifestations of ischemic heart disease (IHD) – myocardial ischemia and angina pectoris, acute myocardial infarction, and sudden cardiac death – is unevenly distributed during the 24 h with greater than expected events during the initial hours of the daily activity span and in the late afternoon or early evening. Such temporal patterns result from circadian rhythms in pathophysiological mechanisms plus cyclic environmental stressors that trigger ischemic events. Both the pharmacokinetics (PK) and pharmacodynamics (PD) of many, though not all, anti-ischemic oral nitrate, calcium channel blocker, and β-adrenoceptor antagonist medications have been shown to be influenced by the circadian time of their administration. The requirement for preventive and therapeutic interventions varies predictably during the 24 h, and thus therapeutic strategies should also be tailored accordingly to optimize outcomes. During the past decade, two first generation calcium channel blocker chronotherapies have been developed, trialed, and marketed in North America for the improved treatment of IHD. Nonetheless, there has been relatively little investigation of the administration-time (circadian rhythm) dependencies of the PK and PD of conventional anti-ischemic medications, and there has been little progress in the development of new generation IHD chronotherapies. Available epidemiologic, pharmacologic, and clinico-therapeutic evidence demonstrates how the chronobiologic approach to IHD can contribute new insight and opportunities to improve drug design and drug delivery to enhance therapeutic outcomes. © 2007 Elsevier B.V. All rights reserved. Keywords: Coronary heart disease; Anti-ischemic drugs; Circadian rhythm; Chronotherapy; Oral nitrates; β-Adrenoceptor antagonists; Calcium channel blockers

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Time patterns in the clinical manifestations of IHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Time patterns in myocardial ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Time patterns in acute myocardial infarction (AMI) . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Time patterns in sudden cardiac death (SCD) . . . . . . . . . . . . . . . . . . . . . . . . . . . Temporal changes in the pathophysiological mechanisms of IHD . . . . . . . . . . . . . . . . . . . . 3.1. Prognostic implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Administration (circadian) time-dependent differences in the pharmacology of anti-ischemic medications 4.1. Oral nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Calcium channel blockers (CCB) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. β-Adrenoceptor antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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This review is part of the Advanced Drug Delivery Reviews theme issue on “Chronobiology, Drug Delivery and Chronotherapeutics”. ⁎ Corresponding author. Tel.: +39 0532 236631; fax: +39 0532 236622. E-mail address: [email protected] (F. Portaluppi).

0169-409X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2006.07.029

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Chronotherapy of IHD . . . . . . . . . . . . . . . 5.1. Calcium channel blocker chronomedications 5.2. β-adrenoceptor antagonist chronomedication 6. Perspectives and conclusion . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction The practice of medicine is properly focused on optimizing treatment in the individual patient rather than applying identical therapeutic schemes to all patients afflicted by the same disease. To achieve optimal results, the clinician is accustomed to adjusting the choice of medications and dosages taking into account the patient's ethnicity, sex, age, body mass, stage and severity of primary disease as well as concomitant diseases, other treatments, drug intolerances and allergies, and even patient preferences, among the multitude of factors that ultimately determine therapeutic success or failure. Many factors are known to influence the pharmacokinetics of medications, and hence drug efficacy in the individual patient, and different pharmaceutical formulations may be used to tailor therapeutic strategies to individual needs. Surprisingly enough, very little consideration has yet to be given to a very important factor which may, by itself, represents a significant and often crucial determinant of therapeutic success: time. Since all physiologic functions oscillate rhythmically in time, the activity, toxicity, and kinetics of a medication may depend on its administration time, in relation to the staging of circadian and other biological rhythms. On the other hand, the temporal (biological rhythm) structure of the human body may be altered by disease, leading to significant changes in the response to therapy. Ischemic heart disease (IHD) constitutes a paradigmatic example of the importance of biological time, in terms of the manifestation of the symptoms of myocardial ischemia, onset of severe ischemic heart disease events, and preventive and treatment strategies. In fact, a temporal variation of mainly (but not solely) 24 h is now very well established not only in the level of activity of almost all cardiovascular functions but also in the pathophysiological mechanisms that trigger morbid and mortal cardiovascular events [1]. Biological rhythms of cardiovascular physiology and function give rise to highly predictable temporal variation in the vulnerability to IHD events and to the requirement for and therapeutic response to medications. Herein, we review the epidemiologic, pharmacologic, and clinico-therapeutic evidence found in the scientific literature that demonstrate the utility of a chronobiologic approach in uncovering new insight into the prognostic assessment of IHD as well as improved drug design and drug-delivery strategies for improved patient management and clinical outcomes. The three classes of medications used to treat cardiac ischemic conditions will be taken into consideration: oral nitrates, calcium channel blockers, and βadrenoceptor antagonists. Related issues, such as the chrono-

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therapy of coagulation and hypertension, are addressed in great detail in other contributions to this journal issue. 2. Time patterns in the clinical manifestations of IHD Myocardial ischemia is the underlying pathogenetic mechanism of the cardinal clinical manifestations of IHD. Ischemia of the myocardium may result from either a restricted and insufficient oxygen supply or an increased oxygen requirement. A number of physiologic variables are crucial in determining the discrepancy between the availability and the requirement for oxygen by the myocardium, and predictable temporal changes are exhibited by all of them [2,3]. Quantitatively, circadian (24 h) variations are most prominent, although 7-day, annual, and ultradian (i.e., less than 24 h) periodicities are also well recognized. Such predictable-in-time (biological rhythm) differences in the susceptibility to myocardial ischemia, on the one hand, and in the pathogenetic mechanisms of myocardial ischemia, on the other hand, result in corresponding predictable-in-time differences in the overt expression and manifestations of IHD.

Fig. 1. Twenty-four-hour pattern in ST-segment depression events, i.e., angina pectoris, ascertained by 24-h Holter monitoring of 94 presumably diurnally active IHD subjects. Note the major peak in events ∼ 8 a.m. (08:00) and the somewhat less prominent second peak around bedtime. Shading along the x-axis indicates the presumed sleep span of the sample. Clock time along the x-axis expressed in military units: e.g., 10:00 = 10 a.m.; 16:00 = 4 p. m. Adapted from Deedwania and Nelson [54].

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Fig. 2. Twenty-four-hour pattern in the occurrence of 234 events of ST-segment elevation in a group of presumably diurnally active Prinzmetal variant angina subjects. Events occur primarily during the late evening and early nocturnal sleep span. Shading along the x-axis indicates the presumed sleep span of the sample. Clock time along the x-axis expressed in military units: e.g., 10:00= 10 a.m.; 16:00= 4 p.m. Adapted from Kuroiwa [18].

2.1. Time patterns in myocardial ischemia Myocardial ischemia is a primary feature of IHD. Episodes of transient silent (i.e., non-symptomatic) myocardial ischemia, which are denoted by the ST-segment depression in tracings of the electrical signal of the heart muscle, in untreated patients exhibit a prominent circadian patterning [4–13]. Population based studies reveal that the frequency of transient episodes of myocardial ischemia is at least two-to-three-fold greater in the

morning, during the first few hours of diurnal activity, than it is during the nocturnal sleep span [14]. A secondary vulnerability to transient ischemic episodes is sometimes observed later during the day, between 6 and 8 p.m. (Fig. 1) [15]. In one study on persons with established coronary artery disease, both symptomatic (chest pain) and silent (non-chest pain) episodes of ST-segment elevations were recorded in 72% of patients between midnight and 9 a.m. [16]. Finally, a circadian variation in the ST-segment response to exercise was demonstrated in presumably diurnally active stable angina patients, with greater ST-segment displacements found when exercise is performed at 4 p.m. than at 8 a.m. [17]. The pattern of ischemic events is differently staged during the 24 h in patients with so-called variant angina, i.e., myocardial ischemia which results from vasospasm of the coronary arteries. Episodes of myocardial ischemia in variant angina patients are denoted as ST-segment elevations in the tracings of the electrical signal of the heart muscle. Such ST-segment elevations are much more frequent during the nighttime sleep span, between 2 and 4 a.m. (Fig. 2) than any other time of the day or night [18,19]. Moreover, variant anginal attacks occur more frequently during morning than afternoon exercise [20]. 2.2. Time patterns in acute myocardial infarction (AMI) It is now well established through large-scale population studies that the frequency of AMI onset during the 24 h is lowest during the first part of the night, increased during the second part of the night, and highest during the initial hours of diurnal activity, between 6 a.m. and noon [21–29]. Cohen et al. [30] performed a meta-analysis of the clock time occurrence of 66,635 AMIs reported in 30 published studies. The incidence rate of AMI onset between 6 a.m. and noon was 40% (the relative risk being 1.38) higher than during the rest of the day in presumably diurnally active persons. Based on the metaanalysis, approximately one of every eleven AMIs was found to be attributable to the observed morning excess (Fig. 3).

Fig. 3. Time of day of 66,635 AMI and of 19,390 SCD events summarized according to the respective four 6-h intervals of the day and night. Note the single very prominent peak in both AMI and SCD between 6 a.m. and noon. Clock time along the x-axis expressed in military units: e.g., 10:00 = 10 a.m.; 16:00 = 4 p.m. Adapted from Cohen et al. [30].

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The peak incidence of AMI onset occurs within the first few hours of the activity span [31]. The temporal relationship with awakening also is detected in shift workers with a reversed sleep–wake routine [32]. Subgroups of certain patient groups have been reported to present a different temporal pattern in the onset of AMI events, as suggested by smaller peaks of incidence in the evening [25,26,29] and/or daytime [26,27]. Age [25,26] and gender [26] might affect the circadian onset pattern of myocardial infarction, but this is not a consistent finding [28,29]. A different pattern defined by only a minor evening peak or absence entirely of 24-h variation in infarct onset has been reported in groups of patients with a history of smoking, diabetes [25,26], cardiovascular disease, stroke [29], or previous AMI other than non-Q-wave type [26], congestive heart failure, or non-Q-wave type myocardial infarction [25,26,33]. It is noteworthy that the majority of the published epidemiologic studies have failed to take into account the effects of differences in the sleep–wake routine of the persons who experienced the AMIs (in the United States about 20% of work force is likely to be engaged in night or rotating shift work and adheres to an atypical sleep–wake routine) and of medications and their scheduling on the 24-h pattern of AMI. We will review this latter aspect in detail later on, but it is clear that the persistence of the significant morning peak in AMI occurrence, despite the widespread use of medications which may affect the occurrence of ischemic episodes, suggests that the actual morning risk of AMI is underestimated. Available epidemiologic data also indicate that the current medication and drug-delivery strategies fail to adequately protect vulnerable patients from myocardial ischemic events, especially myocardial infraction and sudden cardiac death, when they are at greatest risk — in the morning during the initial hours of the daily activity period.

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Fig. 4. Twenty-four-hour pattern in the occurrence of 703 SCD in a group of presumably diurnally active coronary diseased persons. Note the occurrence of the major peak in SCD at the beginning of the activity span and the second somewhat less prominent peak in the late afternoon–early evening. Clock time along the x-axis expressed in military units: e.g., 10:00 = 10 a.m.; 16:00 = 4 p.m. Adapted from Arntz et al. [38].

protection obtained with different therapies during the 24 h which result, at least in part, from administration-time differences in drug PK and PD. 3. Temporal changes in the pathophysiological mechanisms of IHD

2.3. Time patterns in sudden cardiac death (SCD) SCD is another, and more extreme, manifestation of IHD. Population based studies also show that SCD exhibits marked 24-h variability in occurrence, with a prominent morning peak between 6 and 11 a.m., a secondary peak in the afternoon, and a trough during the night in presumably diurnally active persons (Fig. 4) [34–40]. A meta-analysis [30] conducted on the time of day of 19,390 SCDs reported in 19 different publications found the incidence rate of SCD to be 29% (relative risk 1.29%) higher in the morning between 6 a.m. and noon compared to the rest of the day. Approximately 1 of every 15 SCDs are attributable to the morning excess in incidence. Again, when subgroups with different aggregations of atherosclerotic risk factors (like hypertension, diabetes, dyslipidemia, and so on) are analyzed, different temporal patterns of occurrence are found. Deaths from fatal arrhythmias and myocardial infarction show a morning and afternoon peak of incidence; whereas, cardiac deaths of diabetic subjects show an afternoon and evening peak [41,42]. Overall, the day–night pattern in the onset of the main clinical manifestations of IHD – transient episodes of silent and nonsilent myocardial ischemia, AMI, and SCD – appears to be the result of the multiple temporal patterns of the various risk factors that concur in each individual patient, as well as the variable

The onset of cardiac ischemic events is triggered by several pathophysiological mechanisms, particularly the sudden increase in the morning of blood pressure (BP), heart rate (HR), sympathetic activity, basal vascular tone, vasoconstrictive hormones, prothrombotic tendency, platelet aggregability, plasma viscosity, and hematocrit. All these variables exhibit rather prominent circadian rhythmicity with phases that are positively correlated with the timing of excesses in ischemic events during the 24 h as discussed in the preceding sections. BP reaches peak values in the morning, although a secondary peak is usually present in the late afternoon or early evening. There is controversy concerning whether the morning surge in BP commences during sleep or just before [43–46] or after awakening [47–50]. At present, it is not possible to decide whether and to what extent the BP rhythm is endogenous in nature, i.e., driven by an internal clock, since no data have yet been obtained from subjects studied under unique free-run conditions in total darkness that enable chronobiologists to determine the origin of 24-h temporal variations. However, in the rat there is evidence that cardiovascular rhythms are controlled by the central clock(s) located in the suprachiasmatic nuclei (SCN) of the hypothalamus, since the rhythms persist under free-run conditions (i.e., in the absence of environmental

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time cues such as the periodic ambient light–dark cycle) and are abolished by lesioning of the SCN [3,51]. Some investigators suggest the existence of two different patterns in BP: one that begins to gradually rise before awakening, which is thought to be especially common in younger persons, and another that starts to rise with physical activity, which seems to be especially common in the elderly [52,53]. In any case, the morning surge in HR and BP results in a markedly increased (by as much as 40%) myocardial oxygen demand at this time of the day [54]. This demand is thought to play a key role in the increased morning risk of IHD events in at-risk persons. More than 80% of the episodes of ambulatory ischemia are associated with substantial increases in HR [55,56]. A circadian rhythm in HR is well established [57–59] with a strong genetic dependence [60] and a relative independence from the sleep– wake cycle [61]. The relative tachycardia that accompanies the morning arousal from nighttime sleep causes increased myocardial oxygen demand [56], and this contributes to the excess morning frequency of ischemic episodes, AMI, and SCD [62]. It is well-known, however, that ischemic events also can occur during sleep, especially in persons with severe coronary artery disease and vasospastic (variant) angina. In addition, myocardial ischemia may be triggered overnight during episodes of rapid eye movement (REM) sleep [63,64]. During so-called non-REM sleep, HR, BP, and sympathetic nerve activity are lower than during wakefulness [65–67]. During REM sleep, on the other hand, HR and BP abruptly rise to levels comparable to the waking state, while sympathetic nervous system activity even surpasses levels seen during the daytime wake state. Hence, REM sleep is a period of potential cardiovascular risk, as demonstrated by its coincidence with reduced coronary blood flow [68] and increased occurrence of coronary spasm [64]. This risk is time-dependent, considering that episodes of REM sleep occur preferentially during the second portion of the nightly rest span. Thus, the timedependent early morning increase in the risk of myocardial ischemia appears to be determined, at least in part, by the circadian rhythmicity in REM sleep propensity through increased levels of HR, BP, and sympathetic activity. Other endogenous circadian rhythms are also involved in the heightened morning-time risk of IHD. Plasma norepinephrine level [69,70] and plasma renin activity [71] induce coronary vasoconstriction, which is elevated during the morning hours. Animal studies show the resting coronary tone is highest in the morning and least intense at night [72]. A circadian rhythm in vascular basal tone is also demonstrated [73], in relation to increased alpha-sympathetic vasoconstrictor activity during the morning. In addition, the ischemic threshold is lower during this part of the day [74], suggesting that ischemia-induced coronary vascular resistance is increased then. This finding is also supported by a similar variation in post-ischemic forearm vascular resistance [74]. Thus, the low ischemic threshold in the morning presumably mirrors the elevated coronary vascular resistance at this time of the day. In addition, the circadian pattern of plasma cortisol secretion, characterized by a sharp morning rise in diurnally active persons [75], contributes to the reduction of the coronary blood flow at this time of the day by increasing the sensitivity of the epicardial vessels to vasoconstrictor stimuli [6].

3.1. Prognostic implications Only a limited amount of data is available on the prognostic implications of the temporal variations in the inducing mechanisms of myocardial ischemia. For example, the (biological) time of AMI onset seems to affect the clinical course and outcome of those who succumb to such events [76]. AMIs that commence in the morning between 6 a.m. and noon are associated with a greater infarct size than those that commence at other times of the day and night; whereas, an onset time between noon and 6 a.m. is associated with a significantly lower risk of circulatory arrests from ventricular arrhythmias than those that commence at other times of the day [77]. Moreover, the circadian time of myocardial infarction affects the success rate of thrombolysis by medications: the success rate of thrombolysis is much poorer in patients who experience AMI onset in the morning than in those who experience an AMI onset at other times of day and night [78]. 4. Administration (circadian) time-dependent differences in the pharmacology of anti-ischemic medications All types of medications may show administration-timedependent differences in their PK and/or PD. This is due to the fact that all functions involved in PK, from drug absorption to drug elimination, are organized in time as circadian rhythms. For example, physiologic variables like gastric emptying and gastrointestinal perfusion are more pronounced in the morning; hence, they exert time-dependent influences on the absorption kinetics of oral medications taken up by passive diffusion. However, medications that are used to treat IHD patients are also bound to be influenced by circadian rhythms in the previously discussed physiopathogenetic mechanisms of myocardial ischemia. Information is available for a number of anti-ischemic medications documenting clinically significant administrationtime differences in their PK and PD. Herein, we will review in detail these temporal issues for three classes of antianginal medications: oral nitrates, calcium channel blockers, and βadrenoceptor antagonists. 4.1. Oral nitrates Administration-time-dependent differences in PK phenomena may be responsible for temporal variations in the efficacy of organic nitrates. The PK of both isosorbide dinitrate (ISDN) and isosorbide-5-mononitrate (IS-5-MN) has been studied in relation to the circadian time of drug dosing in healthy subjects [79–81]. Although no significant administration-time differences were found with ISDN [82] and the slow-release formulation of IS-5-MN [80], the time-to-peak concentrations (tmax) of the immediate release IS-5-MN were significantly shorter with morning than evening dosing [81,83]. However, independent from the galenic formulations of the two IS-5-MN preparations, the concentration–response relationships of the two oral nitrate formulations were time-dependent. After morning dosing, peak effects coincided with peak drug concentrations; whereas, after evening dosing the time-to-peak

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effects occurred significantly earlier than the time-to-peak concentrations [81,83]. The first evidence for a circadian phase-dependency in the action of nitrates was provided in 1979 by the classical study of Yasue et al. [20]. This study was conducted on 13 presumably diurnally active patients with Prinzmetal's variant angina who performed treadmill exercise tests in the early morning between 5 and 8 a.m. and again in the afternoon between 1 and 4 p.m. Exercise-induced angina attacks as well as ECG abnormalities occurred in all 13 subjects during the morning treadmill exercise tests, but they occurred in only two subjects in the afternoon exercise tests. Interestingly, glyceroltrinitrate administration in the morning, versus the afternoon, better prevented angina attacks and exerted greater dilating effect on the coronary vessels, indicating temporal (circadian) variation in vasomotor tone. This study clearly demonstrated for the first time that the risk of exercise-induced coronary spasm is dependent on the time of the day when the exercise challenge is performed. Supporting this hypothesis and the time-dependency of medication effect, the study demonstrated a dramatic increase in the patency of the great coronary arteries by glyceroltrinitrate when ingested in the morning, but not when ingested in the afternoon. Further support for a daily variation in arterial hyperreactivity comes from the study of persons with variant angina pectoris in whom the threshold of ergonovine (an α-adrenoceptor stimulating segale alkaloid)-provoked angina attacks was demonstrated to be lower in the morning than afternoon [84]. Hausmann et al. [13,85] demonstrated in stable angina pectoris that once-daily dosing of ISDN reduced the number of ischemic episodes exclusively during the daytime, but it had no effect during the night, resulting in a flat circadian pattern in myocardial ischemia. Quyyumi et al. [86] compared the antianginal efficacy of atenolol, nifedipine, and IS-5-MN and observed a similar reduction in nocturnal ischemia by each of the medications; whereas, daytime episodes were less affected by nifedipine and the mononitrate compared to atenolol. In patients with stable angina pectoris, the effects of a 20 mg dose of IS-5-MN administered at 12-h intervals twice daily and 120 mg ISDN once daily were compared on ergometric STsegment depression at different circadian times (10 a.m., 2 p.m., and 6 p.m.) [87]. Exercise-induced ST-segment depression appeared to depend on circadian time, the most pronounced depression occurring in the late afternoon [87]. The antiischemic effect of ISDN did not differ between times of exercise testing; whereas, those of IS-5-MN achieved statistical significance only when ergometry was performed in the morning [87]. The lack of anti-ischemic effect of the mononitrate at noon could be due to declining plasma concentrations several hours after drug intake at 8 a.m., to circadian variation in vessel sensitivity to nitrovasodilators, or – most likely – to both of these factors. Considering the above mentioned circadian fluctuations in basal vessel diameter [20] and peripheral resistance [73], with highest vascoconstriction in the early morning, it is understandable that vasodilation by ISDN leads to a more pronounced orthostasis at 2 a.m. than at other times of the day [83]. Two other studies involving the single morning or twice-daily dosing of IS-5-MN documented

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significant reductions in angina attacks; both treatment strategies were equally effective at different times of the day, and thus they did not modify the circadian pattern of angina [82]. Based on the findings of the above reviewed studies, oral nitrates appear to be capable of influencing the circadian distribution of ischemic episodes (Table 1); nonetheless, further studies are necessary to appropriately clarify the mechanisms of such influence. It is not clear whether such influence may vary with different drugs of this class or even with different pharmaceutical preparations, though the formulation may affect the circadian time-dependency of drug PK. Moreover, the important clinical problem of nitrate tolerance has yet to be addressed in relation to the circadian time of drug dosing. 4.2. Calcium channel blockers (CCB) In healthy volunteers, the bioavailability of an immediaterelease formulation of nifedipine was found to be reduced by 40% following evening compared to morning dosing, with peak concentrations (Cmax) being higher and tmax being shorter with morning dosing [83,88]. In contrast, the PK of a sustainedrelease formulation of nifedipine studied in essential hypertensive patients did not depend on the circadian time of dosing [83]. Also, regular [89] as well as sustained-release verapamil [90] displayed higher Cmax and/or shorter tmax values after morning dosing. Available studies on the effects of CCB on the circadian distribution of AMI are limited by the lack of separate analysis on different types of such medications, despite the fact that the anti-ischemic mechanisms of the dihydropiridines differ markedly from that of other CCB. This could explain, at least in part, why alternatively no effect has been found on the 24-h pattern of AMI [24] or that an attenuated early morning peak with an additional peak around midnight [91] were found in at-risk persons treated with any kind of CCB. More consistent results were obtained by studying the effects of CCB on the circadian pattern of myocardial ischemia. In contrast to atenolol, nifedipine did not alter the circadian profile of either the occurrence or duration of ischemic episodes [92]. When metoprolol was administered as a monotherapy or in combination with nifedipine and compared for the effect on transient ischemia [93], metoprolol was found to significantly attenuate the morning peak, while the combination of metoprolol plus nifedipine was found to blunt both the morning and evening peak of ischemia. These results indicate the existence of different ischemic mechanisms at the two different circadian times. This is confirmed by the observation that nifedipine exerted only a minor effect on the occurrence of ischemic events related to HR increases, while ischemia events that were independent of HR changes were markedly reduced [55]. At higher doses, however, both immediate-release [94,95] and controlled-release [96] nifedipine were shown to reduce HR-related ischemic episodes in the morning. It is interesting to note that when the effect of the morning versus evening dosing of extended-release nifedipine was compared [96], the circadian patterns of ischemia showed a residual morning peak after

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reduced ischemic episodes throughout the day and nighttime with once-daily dosing [104,105], like the sustained-release formulations of diltiazem [97] and nifedipine [55]. On the other hand, CCB appear to be minimally effective in controlling most ischemic episodes that are precipitated by HR increase in the morning. This is particularly true for the short-acting and nonsustained-release preparations which may show some efficacy in this respect only at very high dosages. Table 1 summarizes the major findings of studies that have assessed the effect of CCB on the circadian occurrence of IHD symptoms.

evening dosing compared to a steady increase from midnight until the afternoon after morning administration. However, diltiazem, a different type of CCB, reduced more effectively the diurnal HR-related than the nocturnal HR-independent ischemic episodes [55,97]. An aspect which awaits clarification is the possibility that time-dependent differences in the antihypertensive effect of CCB may contribute to the circadian differences in their antiischemic efficacy. Verapamil was found to reduce BP to a greater extent during the day than nighttime [98,99]; whereas, the dihydropiridines seem equally effective following both day and evening administration [100–102]; however, evening dosing of isradipine [103] and amlodipine [102] in non-dipper (mean sleep-time BP decline less than 10–20% of daytime mean BP) hypertensive patients seems to more effectively normalize the pathological (non-dipping) 24-h BP profile. Overall, it appears that the treatment of HR-independent vasospastic ischemia could be restricted to those medications that are effective vasodilators at all circadian times. In fact, amlodipine, a dihydropyridine CCB derivative of long half-life,

4.3. β-Adrenoceptor antagonists In healthy volunteers the concentration–response relationship for propranolol depends on the circadian dosing time [106]. Moreover, the PK of propranolol and oxprenolol have also been shown to depend on circadian dosing time [106–108], with Cmax being higher and tmax being shorter after morning versus evening dosing. Decreases in HR by propranolol and oxprenolol have also been found to be more pronounced during

Table 1 Effects of calcium channel blockers, nitrates, and acetylsalicylic acid (aspirin) on the circadian pattern of symptoms in IHD patients Drug

Calcium channel blockers Amlodipine Amlodipine Diltiazem Diltiazem SR Diltiazem SR Diltiazem SR Nifedipine Nifedipine Nifedipine GITS Nifedipine GITS + beta-blockers

n

Dose [mg], & duration

Nifedipine Nifedipine Nifedipine Nifedipine CC-Blockers CC-Blockers

47 250 13 60 50 50 50 50 92 92 115 33 10 16 9 147 132

5–10, mean 71 d 10, 7 w 90, 2 h 2 × 180, 2 w 350, 2 w 350, 2 w 79, 2 w 79, 2 w 30–180m, 4 w 30–180e, 4 w? 3 × 10–20, 5 d 4 × 10–30, 1 w 3 × 20/30, 2–4 w 3 × 10/20, 5 d ?, ? ?, ?

Organic nitrates ISDN SR ISDN SR IS-5-MN IS-5-MN IS-5-MN IS-5-MN Glyceroltrinitrate Nitrates

15 10 10 187 195 9 7 174

120m, 2 w 10m, 3 w 2 × 20, 3 w 40m, 2 w 2 × 20, 2 w 2 × 40, 5 d 0.6 acute ?, ?

Incidence of ischemia Morning

Daytime

References Night

Diagnosis

( )

CHD, AA CHD, stA CHD, varA CHD, stA CHD, stAa CHD, stAb CHD, stAa CHD, stAb CHD, stA CHD, stA CHD, stA CHD, stA CHD, stA CHD CHDe MId MId

[104] [105] [20] [96] [55] [55] [55] [55] [96] [96]

CHD, stA CHD, stA CHD, stA CHD CHD CHDe CHD, varAf MId

[85] [87] [87] [82] [82] [86] [20] [91]

ø

( )

ø

ø

ø

ø

ø ø

ø

ø ø

ø

[92] [95] [94] [86] [24] [91]

Rating of drug effects: “ ”, “ ”, “ ” = effective, ø = no effect. The following abbreviations are used: CHD = coronary artery/heart disease, MI = myocardial infarction, stA = stable angina pectoris, varA = variant angina, AA = angina attacks, m = morning administration, e = evening administration. a Ischemia associated with heart rate increase. b Ischemia not associated with heart rate increase. c Rhythm in ischemic threshold abolished. d Influence on rhythmic pattern. e Severe angina pectoris. f Increase in coronary artery diameter.

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the daytime hours [106,107]; whereas, no circadian timedependency was found when exercise-induced HR was studied under oxprenolol treatment [108]. β-adrenoceptor antagonists are effective in reducing the risk of AMI. Since the first demonstration of the existence of 24-h variation in the occurrence of AMI, this medication class has been extensively investigated for its protective effect. Several well conducted studies confirmed that β-adrenoceptor antagonists are able to abolish the morning peak in AMI onset [23,24,91], although some studies failed to demonstrate such [86,109–111]. Propranolol selectively decreased excess SCD that occurs in the morning hours, leaving unchanged the frequency of its occurrence during the rest of the day [36]. During the same morning period, atenolol and metoprolol show their maximum ability to reduce sympathetic activation and increase vagal tone [112], both established neural mechanisms that are key to the prevention of myocardial ischemia. Most studies demonstrated the ability of propranolol [113], metoprolol [24,93,114,115], atenolol [92,94], or bisoprolol [116] to abolish or attenuate the morning peak in ischemic events. However, pindolol, a βadrenergic antagonist with intrinsic sympathomimetic activity, increased HR at night and failed to reduce ischemia [109]. An administration-time-dependent effect of β-adrenoceptor antagonists was also demonstrated in ischemic threshold [56] and frequency of ventricular premature complexes, both in persons with normal left ventricular function [117] and in those suffering from AMI [118]. A detailed analysis of data from the Angina and Silent Ischemia Study [55] showed the importance of the subclassification of ischemic events with regard to concomitant changes in HR. In that study, propranolol markedly reduced those ischemic events which occurred while or directly after HR increase; whereas, the proportion of episodes unrelated to HR changes was even more pronounced by β-adrenoceptor antagonist treatment. Moreover, HR-related ischemic episodes exhibited a different circadian pattern than non-HR-related ones; thus, antiischemic treatment affecting only one type of ischemia can definitely be expected to show a circadian time-dependency. Table 2 summarizes the effects of β-adrenoceptor antagonists on the circadian pattern of symptoms in IHD patients. It appears that β-adrenoceptor antagonists effectively reduce ischemic events at any time of the day, but in diurnally active persons they are most effective in the early morning hours, when the risk of clinical manifestation of IHD is greatest. Studies comparing the PK and PD of β-adrenoceptor antagonists following dosing at different times of the day are still lacking in IHD patients. 5. Chronotherapy of IHD The concept of chronotherapeutics, although relatively new to cardiovascular medicine, was first introduced and proven worthy in clinical medicine in the 1960s, when the morning alternate-day corticosteroid tablet dosing schedule was introduced as a means to minimize the adverse effects of such antiinflammatory medications as prednisone and methylprednisolone [119]. Demonstration of significant circadian variations in

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the clinical manifestations and the pathophysiological mechanisms of IHD (as reviewed in Sections 2 and 3 above) warrants the utilization of special drug-delivery technologies to achieve highest blood and tissue concentrations for maximal protection during the time period when myocardial ischemia is of greatest risk and occurrence — the second part of the night and the first hours immediately following the commencement of diurnal activity. Based on this assumption, it should be noted that even the simple bedtime, instead of morning, dosing of once-daily conventional anti-ischemic medications may enhance therapeutic protection. This is particularly true for nitrates administered through transdermal preparations and which cannot cover the entire 24 h; these medications need to be discontinued for a 6–8 h span every day to prevent drug tolerance. By applying the patch at bedtime (as opposed to in the morning, as too often prescribed even today by unaware physicians) and removing it the following day between noon and bedtime, the patient will be well covered during the span of maximum risk. Only a very few conventional medications have been studied for their therapeutic impact and safety when dosed at a different time of the day [80,83,88–90,102,103,106–108,120–125]. Knowledge of the extent to which the safety and therapeutic effect of the majority of conventional once-a-day medications used in IHD are affected by ingestion (circadian) time is far too sparse to support any broad scale practice of bedtime dosing of the large number of available formulations. Instead, more precise synchronization of peak and trough concentrations of anti-ischemic medications with predicted greatest and lowest rate of occurrence of myocardial ischemia is ensured by drugdelivery technology. In the following subsections, we review those specific formulations that are now approved and marketed in the USA as chronotherapies of IHD. 5.1. Calcium channel blocker chronomedications Controlled-Onset, Extended-Release (COER)-Verapamil (USA: Covera HS™; other markets: Chronovera™) constituted the first special drug-delivery tablet IHD and hypertension chronotherapy [126,127]. It was approved in the United States by the Food and Drug Administration (FDA) in 1996 for marketing by the then Searle Pharmaceutical Company. The drug-delivery technology of this CCB tablet medication delays the release of verapamil for approximately 4–5 h following the recommended bedtime ingestion. Medication is released thereafter so highest blood concentration is achieved in the morning between 6 and 10 a.m., with an elevated level sustained throughout diurnal activity. The half-life kinetics of verapamil results in a progressive decline of drug level in the evening and over night, so minimal concentration occurs during the first half of nighttime sleep, when the risk of myocardial ischemia (as well as HR and BP) is low [128]. The circadian pattern of the anti-ischemic efficacy of Covera HS strictly follows the circadian changes in the occurrence of myocardial ischemia, as documented by the finding that it effectively reduces not only the circadian rhythms of BP, HR, and rate-pressure product (RPP = systolic BP × HR), a surrogate measure of left ventricular work and myocardial oxygen demand

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Table 2 Effects of β-adrenoceptor antagonists on the circadian pattern of symptoms in IHD patients Drug

Beta-adrenoceptor antagonists Atenolol Atenolol Atenolol Atenolol Atenolol Atenolol /propranolol Bevantolol Bisoprolol Metoprolol Metoprolol Metoprolol Nadolol Pindolol Propranolol Propranolol Propranolol Propranolol Propranolol LA Propranolol LA Propranolol LA Propranolol β-Blockers β-Blockers β-Blockers β-Blockers β-Blockers

n

23 24 41 15 9 18 21 13 9 10 31 23 15 13 419 9 123 50 50 24 101 135 143 206 132 185

Dose [mg] and duration

59/100m, 4 w 50/100, 2–4 w 100, 5 d 100, 5 d 100, 5 d 25/40 or 80, 2 w 200, 4 w 10m, 2 w 2 × 100/200, 1 w 2 × 200, 1 w 2 × 50/100, 2 w 40/80m, 4 w 3 × 5, 5 d 60, 2 h ?, 6 w 4 × 40, 4 w 85 ± 28, 116 ± 56 w 292, 2 w 292, 2 w 80, 5 d 180/240, 6–12 w ?, ? ?, ? ?, ? ?, ? ?, ?

Incidence of ischemia Morning

Daytime

References Night

( )

( ) ø –

– ( ) ø

ø

( ) ø ø ø

(–) ø ø ø ø

Diagnosis CHD, stA CHD CHD, stA CHD a, AA CHD a CHD, stA b CHD, stA CHD CHD, stA CHD CHD, stA CHD, stA CHD, aa CHD, varA CHD, VA CHD, stA MI c,VA CHD, stA d CHD, stA e CHD, SCD f MI f MI, n-Q f MI f MI, VPC f

[110] [94] [92] [86] [86] [56] [111] [116] [114,24] [115] [93] [110] [109] [20] [118] [17] [40] [55] [55] [113] [36] [23] [33] [24] [117] [91]

In general coronary heart disease was verified by angiography, mostly Holter-ECG was used to assess the ischemic burden, myocardial infarction was verified objectively. If available the number of patients (n), the drug dosage (after titration), the duration of treatment (h = hours, d = days, w = weeks), the time of drug dosing (m = morning, e = evening), the main diagnosis and the reference are given. Though not mentioned in the studies a morning application can be assumed for drugs with once-daily dosing. ”, “ ” = effective, ø = no effect, “–” = worsening. Rating of drug effects: “ ”, “ The following abbreviations are used: CHD = coronary artery/heart disease, MI = myocardial infarction, stA = stable angina pectoris, varA = variant angina, AA = angina attacks, VA = ventricular arrhythmias, VPC = ventricular premature complex, n-Q = non-Q-wave infarction, SCD = sudden cardiac death. a Severe angina pectoris. b Rhythm in ischemic threshold abolished. c Rhythm observed with no antiarrhythmics abolished by propranolol. d Ischemia associated with heart rate increase. e Ischemia not associated with heart rate increase. f Influence on rhythmic pattern.

[129]. Its side-effect profile is similar to that of placebo, and it is as effective in African Americans as it is in Caucasians [129]. Moreover, the dosing of Covera HS formulation as recommended, at bedtime, compared to the recommended morning dosing of the CCB Nifedipine GITS formulation, which utilizes a special drug-delivery system to achieve near-constancy in drug concentration throughout the 24 h, achieves significantly better RPP control in the morning when the ischemic risk is highest [130]. However, it has to be kept in mind that in this study Covera HS was consistently ingested in the evening; whereas, Nifedipine GITS was always ingested in the morning [130]. Thus, this study design does not allow a direct chronopharmacological comparison between the two treatments. Chronotherapeutic Oral Drug Absorption System (CODAS)Verapamil: A second special drug-delivery CCB, CODAS-verapamil (Verelan PM™; Schwarz Pharma) was approved in the United States by the FDA in 1999; however, it was approved only

for the treatment of hypertension. Release of verapamil from the polymer-coated beads of this capsule medication following recommended bedtime ingestion is delayed for approximately 4 h. Medication is then dispersed in an increasing amount so that peak drug blood concentration is achieved in the morning, between 6 and 10 a.m. [131]. Two placebo-controlled, paralleldesign, double-blind 24 h ambulatory BP monitoring trials involving mild-to-moderate hypertensive patients document the greatest reduction of BP and HR (hence, the RPP as well) during the initial hours of diurnal activity (6 a.m. to noon), when ischemic risk is highest [132,133]. Verelan PM chronotherapy was well tolerated, the most frequent adverse events being gastrointestinal, primarily constipation. Although this verapamil chronotherapy significantly attenuates the morning RPP, a surrogate measure of left ventricular myocardial work and myocardial oxygen demand, it has yet to be trialed as a viable chronotherapy of myocardial ischemia.

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Graded-Release Long-Acting Diltiazem: (Cardizem LA, Biovail Pharmaceuticals): This medication was approved in the United States by the FDA in 2003 for once-daily dosing either in the morning or evening. Multiple-dose studies [134] show ingestion of the 360 mg dose of Cardizem LA at 10 p.m., before bedtime, results in a kinetic profile which is suitable for the chronotherapy of hypertension and IHD: trough blood diltiazem concentration occurs in the middle of the night, then rises to achieve a maximum in the morning, and maintains an elevated drug level during the afternoon and early evening. A multi-center trial found bedtime Cardizem LA in doses of up to 540 mg/day to be significantly more effective in controlling morning BP, HR, and RPP than the ACE inhibitor ramipril ingested at bedtime in doses of up to 20 mg/day [135]. Cardizem LA has been found to be safe; the incidence of adverse events was dose-independent and comparable to that of the placebotreated groups. The most frequent side effects, independent of dose, were headache (11.7%), upper-respiratory infection (5.6%), and lower-limb edema (5.4%). No episodes of bradycardia and no episodes of first-degree atrioventricular heart block requiring dismissal from the clinical trials occurred in any of the diltiazem-treatment groups [136]. It should be noted, however, that administration of chronotherapeutic formulations like this one at the improper time of the day (i.e., in the morning rather than the evening) results in drug levels in temporal opposition to the expected cardiovascular risk profile (i.e., minimal drug levels occur during the period of highest risk) of the patient, which emphasizes the critical importance of patient and physician compliance to the recommended bedtime dosing of this and other such chronotherapies [136]. 5.2. β-adrenoceptor antagonist chronomedication Propranolol Chronotherapy (Innopran XL™, Reliant Pharmaceuticals): This chronotherapy was approved in the United States in 2003 by the FDA. Multiple-dose study [137] of this capsule medication shows its ingestion at bedtime as recommended results in trough drug blood concentration during the night due to the intentional delay of propranolol release for 4–5 h, peak drug concentration between 4 a.m. and 10 a.m., and an elevated plateau of drug concentration in the afternoon and early evening. Hence, Innopran XL exhibits an appropriate PK for the treatment of IHD and hypertension. However, this particular propranolol chronotherapy is approved in the USA only for the treatment of hypertension; to our knowledge, this formulation has yet to be trialed as an IHD chronotherapy. It is important to mention that the evening ingestion of certain β-adrenoceptor blocker medications, such as propranolol and atenolol which effectively cross the blood-brain barrier, has been shown to attenuate or even abolish the nocturnal secretion of melatonin [138–140]. Melatonin is a hormone produced by the pineal gland; it is a key component of the biological clock network and central to efficient biological and cognitive functioning. Blood and tissue melatonin concentrations exhibit profound circadian rhythmicity. Disruption of the normal circadian melatonin rhythm may result in an altered and abnormal circadian time structure, with symptoms comparable

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to the acute symptoms of jet lag that result from the abrupt alteration of the habitual sleep–wake cycle following rapid transmeridian displacement of travelers across several time zones by jet aircraft [141]. When disruption of the circadian clock becomes recurrent or chronic, as in the case of night and rotating shift workers, it can be associated with an elevated risk of sleep disorders, depression, peptic ulcer, coronary heart disease [142], and possibly other medical conditions, such as cancer [143]. The substantiation of such health risks of career shift workers implies that therapeutic interventions should preserve the circadian time-keeping network and the body's temporal organization. The consequences of a chronically attenuated or altered circadian rhythm of melatonin in patients treated for prolonged periods of time with β-adrenoceptor antagonists at bedtime await appropriate clinical assessment. Altogether, it appears that Covera HS and Cardizem LA, which are approved by the FDA for the management of IHD, evidence enhanced control of myocardial ischemia in the morning (as reflected by the decrease in the RPP, improved tolerance to exercise challenge, and reduction in silent and nonsilent ischemia events as verified by 24-h ambulatory Holter monitoring assessment), when it is most common, without loss of effect during the remainder of the 24 h. Yet, at the present time there are no data to substantiate the hypothesis that these special chronotherapeutic formulations are more effective than conventional ones in the prevention of severe cardiac events (AMI or SCD) in at-risk patients. One draw-back of all of these studies is that the same “chronotherapeutic” medication was not studied in a cross-over design, i.e., morning versus evening dosing, thereby evaluating the same medication in a dosing-time-dependent matter on the circadian rhythms in cardiovascular symptoms. The first proposed large-scale assessment of verapamil chronotherapy was the five-year international multi-center (Controlled Onset Verapamil INvestigation of Cardiovascular Endpoints: CONVINCE) trial involving 15,000 patients with high cardiovascular risk. This trial was designed to compare the degree of BP control and protection against cardiovascular events afforded by a regimen of conventional β-blocker and diuretic medications versus the Covera HS chronotherapy [144]. This communitybased outcomes study, however, was terminated prematurely, not because of inadequate performance of the chronotherapy, but because of financial and corporate considerations of the pharmaceutical company that acquired the rights to the medication. Because the trial was terminated early, there were far too few cardiovascular events to conduct a valid scientific assessment of the advantage, if any, of verapamil chronotherapy [145]. 6. Perspectives and conclusion An increasing amount of evidence now available in the scientific literature clearly establishes that the occurrence of ischemic episodes in IHD is unevenly distributed during the 24 h. These temporal patterns in transient myocardial ischemia, AMI, and SCD result from corresponding temporal variations in the pathophysiological mechanisms and cyclic environmental triggers that elicit these ischemic events. On the other hand,

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both the PK and PD of many, though not all, anti-ischemic drugs have been shown to be influenced by the circadian time of their administration, even though further studies are necessary to better clarify the mechanisms of such influence on different drug classes, drug molecules, and pharmaceutical preparations. The 24-h rhythmic organization of cardiovascular functions is such that the defense mechanisms against IHD are incapable of providing the same degree of protection during the day and night. Instead, temporal gates of excessive susceptibility exist, particularly in the morning and to a lesser extent in the evening, to aggressive ischemia-inducing mechanisms through which overt clinical manifestations may be triggered. When peak levels of critical physiologic variables like BP, HR, RPP, sympathetic activation, and plasma levels of endogenous vasoconstricting substances are aligned together at the same circadian time, the risk of ischemic events becomes significantly elevated. When this is the case, even relatively minor environmental stimuli that are usually harmless, like physical and mental stress, can precipitate the dramatic life-threatening events of AMI or SCD. Accordingly, the requirement for preventive and therapeutic interventions varies predictably during the 24 h. Thus, therapeutic strategies must be tailored to prevent the excessive risk of morning as well as late afternoon IHD events. This implies that the delivery of anti-ischemic medications either alone or in combination needs to be synchronized in time, especially circadian time, in proportion to need as determined by established rhythmic patterns in the risk of myocardial ischemia, and in a manner that will avert or minimize their undesired side effects. The application of modern pharmaceutical technology is required to achieve chronotherapies of IHD medications to ensure high drug concentration at the desired sites of action during the predictable-in-time windows of elevated risk to myocardial ischemia. The formulation and drug-delivery profiles of IHD chronotherapies must also minimize the risk of conventional adverse drug effects, which may be circadian rhythm-dependent, as well as non-conventional drug effects involving the master and peripheral biological clocks and biological time-keeping. Thus far, only a few select chronotherapies of IHD have been developed by the pharmaceutical industry and approved by governmental agencies for marketing. Their relative merit versus conventional therapies in treating IHD remains unresolved since large prospective trials are required to assess their overall advantage over conventional medications in reducing the risk of ischemic events, particularly in the morning and to a lesser extent in the afternoon when risk is greatest, and improving patient quality of life. The premature termination of the CONVINCE trial based purely on business decisions should not be misinterpreted as evidence against the utility of chronotherapeutics. Extensive review of the scientific literature reveals a disappointing paucity of clinical and pharmacologic investigations so far undertaken in this field, despite the promise of better individualization of treatment strategies, improved drug efficacy, better patient tolerance, and hence better therapeutic compliance that seems to be possible through a chronotherapeutic approach of IHD. Future development of chronotherapeutic medications requires proper assessment, including the study of new drug formulations at least after morning and after

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