Pharmacological approaches for the prevention of restenosis after percutaneous coronary intervention

Pharmacological Approaches for the Prevention of Restenosis After

Percutaneous Coronary Intervention Jeffrey Lefkovits and Eric J. Topoi

A large number of drug trials for prevention of restenosis have been conducted with many showing little or conflicting benefit. Antiplatelets such as aspirin, ticlopidine and thromboxane A2 receptor inhibitors have not shown a clear benefit. Similarly, antithrombotics, either acting indirectly such as heparin, or as direct thrombin inhibitors such as hirudin and hirulog, do not prevent restenosis. Trials with ACE inhibitors, HMG-CoA reductase inhibitors and fish-oil supplements have yielded inconclusive results. The antiproliferatives, angiopeptin, trapidil and tranilast have shown some benefit in small-scale studies. Other drug classes of potential benefit include the glycoprotein lib/Ilia receptor antagonists, inhibitors of the early coagulation cascade, calcium channel blockers and nitric oxide donors. Drug research into restenosis prevention has been hampered by problems with the definition of restenosis and the applicability in humans of animal models. Although no single drug has conclusively proven effective yet, the promise of a number of agents, together with other nonpharmacological strategies will likely result in further reductions in the incidence of restenosis. Copyright © 1997 by W.B. Saunders Company

here is no doubt that the single greatest the technique of coronary angioplasty is the occurrence of restenosis. Apart from the toll it exacts from the individual patient, the development of restenosis fuels the eve>increasing cost of health care and is estimated to add at least $1.5 billion per year to health care costs in the United States alone, x The current paradigm for the etiology of restenosis incorporates the processes of thrombus formation and organization, smooth muscle cell proliferation, extracellular matrix formation, and vessel recoil and vessel remodeling (contracture).2-4 This

T limitation still plaguing

multifactorial nature of the development of restenosis has led to a diversity of approaches aimed at modifying and controlling the undesirable vessel response to injury. Of all the various approaches to the prevention of restenosis, trials involving the use of pharmaco 2 logical agents have probably been the most intensively investigated strategy to date. The ease of administering one or more agents during and after angioplasty, together with the ability to target specific biological processes, offers a potentially convenient and mechanistic tool against restenosis. A large number of drug trials, with a broad range of pharmacological agents, have been completed. This review focuses on the completed trials of pharmacological agents for the control of restenosis, providing a frame of reference for the classes of agents tested, as well as critically evaluating the ultimate value of the various agents in the fight against restenosis.

Drugs of Doubtful or No Benefit Unfortunately the field of drug prevention of restenosis is characterized by dozens of trials that have shown little, no, or conflicting benefit in the prevention of restenosis. Tables 1 to 3 provide a listing of several of the classes of drugs that have been evaluated. Collectively, negative findings serve to underscore some important issues regarding the pathophysiology of restenosis, the applicability of experimental results in animal models to From the Department of Cardiology, The Cleveland Clinic Foundation, Cleveland, OH. Address reprint requests to Eric J. Topoi, MD, Chairman, Dept of Cardiology, Desk F25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195-5033. Copyright © 1997 by W.B. Saunders Company 0033-0620/97/4002-000655.00/0

Progress in Cardiovascular Diseases, Vol. 40, No. 2 (September/October), 1997: pp 141-158

141

142

LEFKOVITS AND TOPOL

TABLE 1. Angiographic Trials of Antithrombotic Agents for Restenosis Restenosis Rate

Angiographic

Restenosis

Follow-up (%) Agent and Dose

Definition

Agent

Control

Value

P

->70% stenosis

18%

20%

n.s.

->50%stenosis

38%

39%

n.s.

>-50% stenosis

21%

31%

n.s.

>-50% stenosis

51%

47%

n.s.

Study

Year n

Aspirin White27

1987

157

111 (71)

Schwartz~8

1988

376

249(66)

Dyckmans 2°

1988

203

86(42)

Mufson 21

1988

453

166 (37)

ASA990 mg/dipyridamole 225 mg ASA990 mg/dipyridamole 225 mg ASA 1500 mg vASA 320 mg ASA 1500 m g vASA 80 mg

1987 1988 1990

157 189 266

119(76) 189 (100) 244 (92)

Ticlopidine 750 mg Ticlopidine 200 mg Ticlopidine 200 mg

->70% stenosis 29% >-50% stenosis 27% Loss of 50% gain 50%

20% 38% 41%

n.s. n.s. n.s.

575 (89) 705 (59)

GR32191 80 mg GR32191 40-80 mg

Loss >-0.72 mm >-70% stenosis

21% 28%

19% 31%

n.s. n.s.

Ticlopidine White 27 Kitazume2a Betrand29 Throboxane A 2

blocker serruys3° 1991 649 Feldman31 1992 1192 Prostacyclin and

analogues 1990 1993

270 247

224 (83) 211 (85)

Prostacyclin 5 ng/kg/min Ciprostene 120 ng/kg/min

->50% stenosis ->50% stenosis

27% 26%

32% 38%

n.s. n.s.

Ellis45 Faxon50 Cairns 5~

1989 1994 1994

4i 6 458 653

259 (61) 394 (86) 633 (97)

>-50% stenosis 29% Loss of 50% gain 52% Loss of 50% gain 47%

37% 51% 47%

n.s. n.s. n.s.

Lablanche52

1995

354

322 (91)

Heparin targeted to aPTT Enoxaprin 40 mg Enoxaparine 30 mg SQ twice daily 6 wks Fraxiparine 0.6 ml/d subcutaneous for 3 mos

>-50% stenosis

38%

n.s.

Hirudinl-3dvheparin*

MLDcomparison 1.51mm 1.54mm n.s.

Knudtson 35 Raizner34

Heparins

41%

Direct thrombin inhibitors Serruys58

1995 1141

986(86)

AbbreviationS: ASA, aspirin; MLD, minimal luminal diameter; n.s., not significant. *Hirudin given as a 40-mg bolus followed by 0.2 mg/kg/h intravenous infusion for 24 hours and subcutaneous placebo twice daily for 3 days or 40 mg bolus followed by 0.2 mg/kg/h intravenous infusion for 24 hours and 40 mg subcutaneous twice daily for 3 days. Heparin given as a 10,000 IU intravenous bolus followed by 15 IU/kg/h intravenous infusion for 24 hours. Modified and reprinted with permission from Mak K-H, Topoi EJ: Clinical trials to prevent restenosis after percutaneous coronary revascularization. Annals of the New YorkAcademy of Sciences 811:255-288, 1997.

human beings, and the interpretation of clinical trials in general. There is little point in discussing each of these trials individually. Rather, a selected number of trials are highlighted to serve as examples for the broader issues they represent.

Aspirin and Other Antiplatelet Agents Even successful angioplasty involves significant vessel injury, with plaque fracture and splitting, medial disruption and vessel stretching? -7 with platelet deposition and mural thr0mbus formation ensuing to varying degrees. 8,9 Platelet activation during angioplasty has been well described in both animal models 5,t° and in human beings 1~ and plays a central role in intracoronary thrombus formation and acute closure associated with coronary angioplasty. Platelets also appear to be

integral components in the process of smooth muscle cell hypertrophy and proliferation that occurs as a response to vessel injury. 12-t4 The use of aspirin during angioplasty is now routine, having been shown to reduce the incidence of acute ischemic complications.l~,J6 Yet. despite the theoretical advantages of platelet inhibition for the control of smooth muscle cell proliferation, aspirin has not shown any corresponding benefit in the prevention of restenosis. ~649 Comparisons between low- and high-dose aspirin have also failed m show any dose response. 2°-22 whereas a meta-analysis of 573 patients treated with various doses of aspirin did not show a significant benefit on the incidence of restenosis. 23 Alternative oral antiplatelet agents such as ticlopidine have proven effective in patients with

143

PHARMACOLOGICAL APPROACHES TO RESTENOSIS

TABLE 2. Angiographic Trials of Lipid Lowering Agents for Restenosis Angiographic Follow-up (%)

. Agent and Dose

Restenosis Definition

Agent (%)

Control (%)

P Value

(50) (79) (100) (62)

Lovastatin 20 mg/d Lovastatin 80 mg/d Pravastatin 20 mg/d Lovastatin 40 mg/d + Probucol 1 g/d

>-50% stenosis >-50% stenosis >-50% stenosis % lumen loss

12 39 41 27

45 42 52 28

<0.001 n.s. n.s. n.s.

82 (100)

Omega-3 fatty acids 5.4 g Omega-3 fatty acids 3.0 g Omega-3 fatty acids 6.0 g Omega-3 fatty acids 6.9g Omega-3 fatty acids 2.2 g Omega-3 fatty acids 4.5 g Omega-3 fatty acids 3.0 g Omega-3 fatty acids 3.2 g Omega-3 fatty acids 8.0g Omega-3 fatty acids 5.4 g

>-50% stenosis

19

46

0.007

Loss of >50% gain

34

33

n.s.

>-70% stenosis

34

23

n.s.

>-50% stenosis

34

20

n.s.

Loss of 50% gain

11

30

n.s.

>-50% stenosis

31

48

n.s.

Loss of 50% gain

21

18

n.s.

>-50% stenosis

33

35

n.s.

>-50% stenosis

52

46

n.s.

Loss of 50% gain

47

46

n.s.

Study

Year

n

HMG-CoA reductase inhibitors Sahni 67 Weintraub72 YuiTM Cavero73

1990 1994 1995 1995

157 404 208 239

Fish oils Dehmer81

1988

82

Grigg86

1989

108

100 (93)

Reis 87

1989

186

56 (30)

Cheng 88

1990

50

43 (86)

Nye84

1990

73

69 (95)

Bairati 85

1992

119

119 (100)

Bellamy163

1992

120

113 (94)

Franzen89

1993

200

129 (65)

Leaf92

1994

551

447 (81)

Cairns51

1994

668

590 (88)

79 321 208 147

Abbreviation: n.s., not significant. Modified and reprinted with permission from Mak K-H, Topoi EJ: Clinical trials to prevent restenosis after percutaneous coronary revascularization. Annals of the New YorkAcademy of Sciences 811:255-288, 1997.

cerebral ischemia, 24,25 and more recently, in the prevention of coronary stent thrombosis. 26 The mechanism of action of ticlopidine is not as clearly understood as for aspirin, although it appears to interfere with the interaction between fibrinogen and its platelet receptor. Ticlopidine has been evaluated in several restenosis trials. 27-z9 Although comparison of these trials is confounded by inconsistent dosing regimens, the use of adjunctive agents, and varying definitions of angiographic restenosis, no significant benefit with ticlopidine has been shown overall. Similarly, agents targeted specifically against the platelet thromboxane A2 receptor 3°32 and administration of the platelet aggregation inhibitor, prostacyclin or its analog, 33"36have not shown a clear benefit in restenosis prevention. More recently, a new class of antiplatelet agents that directly inhibit the platelet glycoprotein IIb/IIIa receptor have been evaluated in the setting of coronary angioplasty. These agents are much more potent platelet

inhibitors and appear to have a different effect on restenosis than the other antiplatelet agents previously discussed. The glycoprotein IIb/IIIa receptor antagonists will be discussed separately.

Anticoagulants As emphasized, mural thrombus formation at the site of vessel wall injury plays a central role in the pathogenesis of restenosis. Although the initial thrombus is platelet-rich, the high concentration of thrombin present at the injury site also results in active fibrin formation. The process of thrombus organization (myofibrotic response) and the presence of thrombin itself appear to be major components of the restenotic process. Thrombin is a potent stimulator of smooth muscle cell proliferation,37,38 and there are experimental data to support an antiproliferative role for thrombin inhibition. 39 Although the logical corollary is that antithrombin agents may help reduce the inci-

144

LEFKOVITS AND TOPOL

TABLE 3. Angiographic Trials of Anti-Proliferative Agents for Restenosis Angiographic Follow-up (%)

Study

Year

n

Steroids Rose°a Stone94

1987 1989

66 102

57 (88) 54 (53)

Pepine95

1990

722

513 (71)

Trapidil Okamoto112

1992

90

Nishikawa 113

1992

160

137 (86)

Maresta TM

1994

254

189 (74)

1993

124 6

1084 ( 8 7 )

Emanuelsson 12a 1995

553

423 (76)

Eriksen lm

1995

112

94 (84)

1995

205

205 (100)

Angiopeptin Kent122

Tranilast Ueda~lr

72 ( 8 0 )

Restenosis Definition

Agent (%)

Control (%)

P Value

Medro148 mg Methylprednisolone 125 mg IM + prednisoione Angiopeptin 5 days 60 mg/d 7 days Methylprednisolone lg

->50% stenosis >-50% stenosis

33 59

33 58

n.s. n.s.

->50%stenosis

43

43

n.s.

Trapidil 600 mg v ASA 300 mg Trapidi1200 mg t.i.d. v dipyridamole 50 mg t.Ld. Trapidil 300 mg v ASA 300 mg

Loss of 50% gain

19

42

n.s.

Loss of 50% gain

20

38

Loss of 50% gain

24

40

<.01

Angiopeptin 190-300 ~Jg/d, 10 days Angiopeptin 4d SQ infusion* 60 mg/d 7 days SQ infusion1"

->50%stenosis

35-38

39

n.s.

->50% stenosis

37

36

n.s.

->50%stenosis

12

40

Tranilast 600 mg/d

Loss of 50% gain

22

46

Agent and Dose

.024

.003 <.01

Abbreviations: ASA, aspirin; SQ, subcutaneous injection; IM, intramuscular injection; n.s., not significant; t.i.d., three times daily. *Angiopeptin administered as 3 mg subcutaneous infusion 6 to 24 hours before, 1.5 mg bolus just prior, and 3 mg/d for 3 days after PTCA. l"Angiopeptin administered as 750 pg/d subcutaneous infusion 24 hours before, 375 tJg bolus just prior, and 750 pg/d for 4 days after PTCA. Modified and reprinted with permission from Mak K-H, Topoi EJ: Clinical trials to prevent restenosis after percutaneous coronary revascularization. Annals of the New YorkAcademy of Sciences 811:255-288, 1997.

dence of restenosis, this has not been borne out in clinical evaluation. The most widely used antithrombin, heparin, has broad actions that extend to involve several other mechanisms that may be important in the restenosis process such as counteraction of platelet-derived growth factor and direct inhibition of smooth muscle cell proliferation. 4° It is now reasonably well established that heparin anticoagulation reduces the risk of abrupt closure during the actual angioplasty procedure, 4]-44 although its role in the early postprocedure period is more controversial. 45,46In contrast, there is no definitive evidence to support a role for heparin in the prevention of restenosis. Although one small study did find a reduction in the rate of angiographic restenosis, 4r this finding was not confirmed in two subsequent and larger trials.45,4s The low molecular weight heparins (LMWHs)

differ from unfractionated heparin because of relatively greater activity against activated factor X and less antithrombin Ill activit)a They also have greater bioavailability than heparin because of less binding to plasma proteins, resulting in more predictable plasma levels. 49 These agents, too, have been investigated in the setting of coronary angioplasty. The first published largescale clinical trial was the Enoxaprin Restenosis (ERA) Trial. 5° In this placebo-controlled trial involving 458 patients undergoing routine coronary angioplasty, enoxaprin or placebo was administered subcutaneously for 1 month postprocedure. There were no differences in angiographic or clinical outcomes among the two groups, assessed at 6 months. The same agent was also used in the Enoxaprine and Maxepa for the Prevention of Angioplasty Restenosis (EMPAR) trial. 5. A smaller dose of the drug was used in this

145

PHARMACOLOGICAL APPROACHES TO RESTENOSIS

study, although the administration was extended out to 6 weeks rather than 4 weeks. However, once again, no benefit was shown on the incidence of restenosis. In the more recent Fraxiparine Angioplastie Coronaire Transluminale (FACT) trial, 52 354 patients were given daily subcutaneous injections of either fraxiparine or placebo for 3 months after successful angioplasty. No differences in angiographic restenosis rates were observed at 3 months, and clinical outcomes were similar in the two groups at 6 months. Thus, despite the variations in activity and pharmacokinetics among standard and low-molecular-weight heparins, none of these antithrombins appears to be effective at preventing restenosis. Alternative antithrombins have recently become available in the clinical arena. The direct thrombin inhibitors directly block thrombin activity, preventing the formation of fibrin from its precursor, fibrinogen. The prototype direct antithrombin, hirudin, is derived from the saliva of the leech and is the most potent inhibitor of thrombin known. As antithrombins, these agents offer several potential advantages over heparin. They are not dependent on antithrombin III, do not become protein bound, and have activity against clot-bound thrombin. 53 Comparative studies have shown hirudin to be more effective than heparin in reducing both platelet and fibrin thrombi in various animal models of experimental angioplasty. 5456 Hirudin has also shown an antiproliferative effect, preventing restenosis at 28 days in a rabbit angioplasty model. 57 Two large-scale trials have now been completed evaluating the effect of direct thrombin inhibition on restenosis. The Hirudin in a European Trial Versus Heparin in the Prevention of Restenosis after PTCA (HELVETICA) triaP 8 determined the effect of 1 to 3 days of hirudin therapy after angioplasty on ischemic events and angiographic restenosis. A total of 1,141 patients were enrolled. Although early ischemic events were significantly reduced with hirudin therapy, no differences in the incidence of ischemic events or angiographic restenosis were found between the hirudin and heparin groups after 7 months' follow-up (Fig 1). Notably, a substantial proportion of the dose of hirudin was administered subcutaneously (rather than intravenously), and this has been suggested as a possible explanation for the lack of efficacy observed with hirudin. Yet, a much larger trial

% Pts

401 A

20

t

10 I

k 6 Month Events

4 Day Events

6 Month Angiographic Restenosis

% Pts

6

B

0 Death

MI

CABG

Composite

Fig 1. (A) Outcomes from the HELVETICA trial. 5s Hirudin treatment resulted in lower ischemic event rates at 4 days (P = .023), but there were no differences in 6-month ischemic events or rates of angiographic restenosis among the three treatment groups at 7 months' follow-up. [] Heparin, n = 382; [] Hirudin IV, n = 381; [] Hirudin IV + SQ, n = 378. (B) Results from the Hirulog in Angioplasty Trial. s9 Hirulog was no more effective than heparin in reducing the incidence of death, myocardial infarction, or need for coronary artery bypass surgery following routine coronary intervention. [] Hirulog, n = 2,053; [] Heparin, n = 2,035.

using hirulog also failed to show any improvement in restenosis 59 (Fig 1). In this trial, 4,098 patients with unstable or post-infarct angina randomly received hirulog or heparin for up to 20 hours after coronary angioplasty, Bleeding rates were lower in patients receiving hirulog, but only a trend toward improved outcomes was noted at 6 months (20.5% hirulog v 25.1% heparin). Whether direct antithrombins will ever find a place as conjunctive therapy for coronary angioplasty will depend on further evaluation and analysis of their

146 cost effectiveness in reducing early ischemic and hemorrhagic events. However, they do not currently appear to have any role in the prevention of restenosis.

Angiotensin Converting Enzyme Inhibitors Although the hemodynamic and left ventricular structural effects of angiotensin converting enzyme (ACE) inhibitors are well known, these drugs have also been investigated as antiproliferatives. Induction of ACE occurs after vascular injury,6° with angiotensin II being implicated in the local response to vascular injury. 61,62The ACE inhibitor cilazapril appeared effective at inhibiting myointimal proliferation in a rat carotid artery model 61,62and has subsequently gone on to largescale evaluation in two human restenosis trials. The European Multicenter European Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) 63 and the larger American MARCATOR (Multicenter American Research Trial with Cilazapril after Angioplasty to Prevent Transluminal Coronary Obstruction and Restenos i s ) 64 trials evaluated cilazapril in a total of 2129 patients undergoing coronary angioplasty, Despite the encouraging results with this agent in animal models, 61,62no benefit in clinical or anglographic restenosis was shown in the smaller European trial. 63 The dose chosen in the MERCATOR trial has been criticized given that the weight-adjusted doses used in the positive animal studies were comparatively much larger. However, even with the higher doses used in the larger MARCATOR trial, cilazapril-treated patients did not have any improvement in clinical events or angiographic restenosis. Alternative ACE inhibitors such as fosinipril have also been tested in the setting of angioplasty, with similarly negative results. 65 The discrepant results between the animal and human studies may reflect differences in administration protocols of the drug. Pretreatment with cilazapril up to 6 days before the vessel injury was found to result in the greatest reduction in myointimal proliferation in the rat model. 6~ In contrast, treatment was initiated only 18 hours before the angioplasty in the clinical trials. Additionally, the doses used in the human trials may have been insufficient to adequately inhibit tissue ACE activity--an action

LEFKOVITS AND TOPOL

that may be more important than inhibition of plasma ACE in preventing neointimal proliferation. 66

Lipid LoweringAgents The demonstration of a reduction in angiographic restenosis by the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, lovastatin, 67heralded significant interest in the potential benefit of these drugs in coronary angioplasty (Table 2). This is despite the observations that lipid deposition does not play an important role in restenotic lesions and that hyperlipidemia, per se, has not been found to be a risk factor for development of restenosis. 68 However, lipidlowering agents can also restore endothelial function, 69 inhibit smooth muscle cell proliferation, 7° and reduce platelet and red blood cell aggregation. 71 Since those encouraging findings of Sahni et al, 67 larger and more recent trials have not confirmed any benefit of the HMG-CoA reductase inhibitors in the prevention of restenosis. Lovastatin, the agent used in the study by Sahni et al, was not found to reduce restenosis or improve clinical outcomes following angioplasty in a larger trial of 157 patients. 72 This was despite a greater than 40% reduction in low-density lipoprotein (LDL) cholesterol levels. The addition of the antioxidant probucol to lovastatin therapy did not improve restenosis rates compared with placebo in another trial. 73 The related agent pravastatin was similarly ineffective.TM In contrast to the HMG-CoA reductase inhibitors, fish oil supplementation has been associated with promising but somewhat controversial findings. The omega-3 fatty acids have been considered antiatherogenic through a variety of potential mechanisms. Decreases in membrane arachidonic acid and thromboxane A2 concentrations, 75,76decreased platelet aggregation, 7<77 anti-inflammatory properties, TM and direct inhibition of neointireal proliferationr9,8° have all been observed with omega-3 fatty acids. Of the nine early trials of fish oil in coronary angioplasty, five showed a beneficial effect on restenosisy -s5 whereas the remaining four did not. 86"89Differences in study design, including the lack of blinding in some, different formulations and doses of fish oil, the absence of pretreatment in some of the studies and nonuniform definitions of restenosis and periods of

147

PHARMACOLOGICAL APPROACHES TO RESTENOSIS

follow-up may have all contributed to the disagreement among these studies. 9° In a meta-analysis of seven of these trials, the dose of omega-3 fatty acids used emerged as an important determinant of restenosis. 91 This same meta-analysis observed a modest but statistically significant benefit of fish oil on restenosis, although the investigators did conclude that this result required confirmation in a randomized trial of sufficient power. 91 Large randomized trials have since been performed to provide a more definitive evaluation of the benefit of fish oils. Preliminary results from the Enoxaprine and Maxepa for the Prevention of Angioplasty Restenosis (EMPAR) trial did not show any significant differences in angiographic restenosis rates between patients receiving fish oil and placebo. 51 In the largest randomized trial to date, Leaf et al reported the 6-month anglographic follow-up in 447 patients receiving fish oil supplementation after angioplasty.92 A large dose of omega-3 fatty acids was used (8 g/day), yet overall patient compliance was deemed to be good as determined by measurement of incorporation of the fatty acids in plasma and red blood cell phospholipids. Nevertheless, no effect on angiographic restenosis rates was found. Interestingly, the investigators of this trial noted that when their results were added to the earlier metaanalysis by Gapinski et al,91 a statistically beneficial effect was no longer apparent. 92 Overall, fish oils do not appear to be effective at preventing restenosis, and the trial experience with these agents has served to highlight the potential limitations of small, underpowered trials and associated meta-analyses.

Other Agents Particular focus has been given to agents that reduce the inflammatory response, potentially preventing neointimal formation (Table 3). Three randomized trials have been completed with corticosteroids. 93-95 Although different formulations and doses of steroid agents were used, no reduction in the incidence of restenosis was observed. The antimitotic agent colchicine has a number of secondary actions that include inhibition of chemotaxis and collagen formation and prevention of platelet aggregation. Yet, it too has been. found ineffective at preventing restenosis. 96,w In contrast, trials with the antiprolifera-

rives angiopeptin, trapidil, a n d tranilast have shown some benefit. The use of these agents will be discussed more fully in the next section.

Drugs With Potential Benefit Platelet Glycoprotein IIb/IIIa Receptor Inhibitors Unlike the other antiplatelet agents already reviewed, platelet glycoprotein IIb/IIIa receptor inhibitors have an impact on the recurrence of ischemic events after angioplast)~ The glycoprotein (GP) IIb/IIIa receptor inhibitors are a pharmacologically diverse group of drugs that block the platelet GP IIbflIIa integrin on the surface of activated platelets. This platelet membrane receptor mediates the binding of fibrinogen between adjacent platelets, forming cross-bridges, which ultimately results in aggregation of the platelets. The GP IIbflIIa receptor forms the final common pathway to platelet aggregation and unlike other antiplatelet agents, the GP IIb/IIIa receptor inhibitors can prevent platelet aggregation irrespective of the agonist initiating platelet aggregation. 9s The first large-scale trial of these drugs in the setting of PTCA was the Evaluation of c7E3 for the Prevention of Ischemic Complications (EPIC) trial. 99,1°° A bolus and 12-hour infusion of the monoclonal anti-GP IIb/IIIa antibody, chimeric 7E3 (now called abciximab) was found to reduce ischemic complications after high-risk angioplasty. The bolus and infusion of c7E3 also resulted in a 26% reduction in the incidence of clinical restenosis at 6 months z°° (see Fig 2). Although angiographic restenosis was not evaluated in this trial, the rate of target vessel revascularization, which is considered a likely barometer of angiographic resten0sis, was reduced by 36%. This ability of a short-term infusion of an antiplatelet agent to reduce adverse clinical events at 6 months has led to the concept of vessel wall passivation, whereby an arterial surface that would normally support platelet deposition at the site of injury is somehow transformed into a Surface that no longer facilitates platelet deposition. The 6-month findings in the EPIC trial are further supported by experimental data showing direct antiproliferative effects associated with glycoprotein IIb/IIIa receptor blockade.i°1 Although certainly of great interest, the EPIC

148

LEFKOVITS AND TOPOL

1.0

LU O Z

0.9

0.8

8 0.7 LL 0.6 0

1'

2~

3~"

4'

5'

-~

Months from Randomization

Fig2, Kaplan-Meier plot of 6-month composite clinical endpoint event rates from the EPIC trial. 100 The composite endpoint comprised death, myocardial infarction, or elective repeat revascularization. A bolus and 12-hour infusion of the platelet glycoprotein lib/Ilia receptor antibody, chimeric 7E3, significantly reduced the incidence of clinical restenosis by 26%. (Reprinted with permission from Topoi EJ, Califf RM, Weisman HF, et al: Randomised trial of coronary intervention with antibody against platelet lib/Ilia integrin for reduction of clinical restenosis: Results at six months. Lancet 343: 881-886, 1994. Copyright © 1994 by the Lancet Ltd.)

trial did not directly show a positive effect of GP IIb/IIIa receptor inhibition on angiographic restenosis. A more recent trial of the GP IIbfllIa receptor inhibitor Integrilin in PTCA included a subset of patients who underwent angiographic follow-up at 6 months. The Integrilin to Minimize Platelet Aggregation and Prevent Coronary Thrombosis (IMPACT-II)102 randomized over 4,000 patients to receive a bolus and either high- or low-dose infusion of Integrilin or placebo bolus and infusion while undergoing coronary angioplasty. This trial failed to show a major benefit on early (30-day) ischemic events rates among Integrilin-treated patients, although there was a strong trend toward benefit, especially in those patients who received the low-dose Integrilin regimen. It is noteworthy that both low- and high-dose Integrilin treatments did significantly decrease ischemic events during the first 24 hours---the period in which the infusions were administered: At 6 months, no significant differences in ischemic event rates were observed among patients receiving Integrilin and placebo. The overall lack of benefit on clinical restenosis was mirrored in the 6-month angiographic follow-up substudy. There were no differences in restenosis rates among the treatment groups, and in fact, there was even a trend toward larger luminal dimensions in the placebo group. The resuhs of the

Randomized Efficacy Study of Tirofiban (MK383) for Outcomes Restenosis (RESTORE) trial, which evaluated the GP IIb/IIIa receptor antagonist, Tirofiban in coronary angioplasty, have also been recently reported. 1°3 As with Integrilin, this peptide-based, highly GP IIb/IIIa-specific drug did not significantly reduce restenosis rates. A number of explanations have been put forward to account for the apparently contradictory results of the EPIC trial with subsequent GP IIb/IIIa receptor inhibitor trials. The EPIC trial only included high-risk patients, whereas IMPACT-II and RESTORE included all patients undergoing routine coronary intervention. The agents chimeric 7E3, Integrilin and tirofiban differ in many respects with regard to their pharmacological properties, affinity for the GP IIb/Illa receptor and plasma half life. Of particular note is that chimeric 7E3 is relatively non-specific for the GP IIb/IIIa receptor, having activity against a number of other integrins, most notably the 0~v[33integrin. 9s This integrin acts as a receptor for vitronectin and has also been implicated in the process of restenosis.l°4 In contrast, Integrilin and tirofiban are highly specific for the GP IIb/Illa receptor, with very little activity against other integrins. Third, the EPIC trial did not provide any data on angiographic measures of restenosis, leaving the question of the correlation between clinical and angiographic restenosis unanswered. The issue has been clouded further by the recently published findings of the Evaluation of PTCA to Improve Long-Term Outcome by c7E3 Glycoprotein Receptor Blockade (EPILOG) trial.i°5 As in the EPIC trial, this study evaluated chimeric 7E3 in the setting of coronary angioplasty but extended its use to routine coronary intervention. The 30-day outcome results once again showed a clear benefit of chimeric 7E3 in preventing early ischemic complications. However, in contrast to the EPIC trial, the 6-month outcomes in EPILOG were not substantially different in patients treated with placebo or abciximab. Angiographic follow-up was also obtained in a subgroup of patients in EPILOG and showed no differences in angiographic restenosis rates among the placebo and abciximab treated patients. The discrepant medium-term results of the EPIC and EPILOG trials may be accounted for, in part, by differences in patient populations and study protocols of the two trials. There was also an approximate 10%

PHARMACOLOGICAL APPROACHES TO RESTENOSIS

improvement in outcomes in the placebo group of the EPILOG trial compared with the placebo group of the EPIC trial, whereas outcomes in the abciximab groups in the two trials were similar. Consequently, the reduction in adverse outcomes in the placebo group made it more difficult to show a statistically meaningful difference between the placebo and abciximab groups in EPILOG. Despite these mitigating explanations, the EPILOG trial still failed to confirm the benefit of abciximab on restenosis observed in the EPIC trial and has left the question of conclusive benefit in preventing restenosis unresolved.

"New" Anti-Proliferative Agents Trapidil. Platelet-derived growth factor (PDGF), as one of a number of mitogens implicated in the vascular injury response, is a target for control of smooth muscle cell proliferation. Although the most obvious source of PDGF is the or-granules of degranulating platelets, PDGF is also derived from activated endothelium, 1°6monocyte-derived macrophages, or even intimal smooth muscle cells themselves. 1°7 Both in vitro and in vivo models have shown the proliferative action of PDGE 14,i°8 Conversely, inhibition of PDGF can result in prevention of smooth muscle cell proliferation, i°9,ii° The agent trapidil (triazolopyrimidine), a competitive antagonist of the PDGF receptor as well as a thromboxane A2 inhibitor, m has already undergone trials in human beings (Fig 3). In an early study, Okamoto et al showed a reduction in angiographic restenosis from 42% in the control group to 19% with the administration of trapidil at a dose of 200 mg, three times daily, n2 Nishikawa et al obtained similar results in a trial of 137 patients, n3 In the largest trial to date, Maresta et al showed a significant reduction in restenosis from 40% to 24% with trapidil at a dose of 100 mg, three times daily, ii4 Although the total number of patients teSted is still small, these series of trials have indicated a potential benefit of PDGF inhibition following angioplasty. Despite the increasing focus On factors such as mural thrombus and vessel recoil in the pathogenesis of restenosis, these findings also serve to highlight the continuing importance of smooth muscle cell proliferation. Larger trials with trapidil are ongoing. Tranilast. Interesting preliminary results have been obtained with the use of the antiallergic

149 agent tranilast for the prevention of restenosis. This agent has shown potent antiproliferative effects in vitro, with inhibition of smooth muscle cell migration and collagen synthesis, uS,n6 In a case-control study, 100 patients administered tranilast for 3 months after coronary angioplasty were compared with 105 control lesions. Restenosis rates were significantly lower at 3 and 6 months in the tranilast group, lit Further study with this novel agent is still required. Angiopeptin. Angiopeptin is a somatostatin analog that has been found to reduce the neointireal response after balloon injury in a variety of experimental models, ua-12° Its mechanism of action is presumably through modulation of growth factor activity secondary to inhibition of insulinlike growth factor-1. In an early pilot study in 112 patients, Eriksen et al showed that a 5-day continuous subcutaneous infusion of angiopeptin reduced the rate of angiographic restenosis from 40% to 12%. No significant differences in adverse outcomes were noted, although patients treated with angiopeptin tended to have a lower incidence of ischemic events. 12i In a larger muhicenter study of 1,246 patients, no significant effects on angiographic restenosis or clinical outcomes were observed with angiopeptin. 122 However, this study has been criticized for using a potentially suboptimal dosing regimen. Angiopeptin has a short half-life, and administration in twice daily subcutaneous injections rather than as a continuous infusion may have resulted in insufficient plasma levels. In a third clinical trial in 553 patients, i23 angiopeptin was administered as a continuous infusion for 4 days, but at a higher dose than used in the study by Eriksen et al. ui Angiographic restenosis rates were 36% in the angiopeptin group and 37% in placebo patients. However, a significant reduction was noted in clinical event rates at 12 months--principally the rate of revascularization procedures. The investigators suggested that the discrepancy between clinical and angiographic findings may relate to the limitations of quantitative angiography or possible nonangiographic effects of angiopeptin such as restoration of endothelial function, i23 Overall, the somewhat contradictory results of these clinical trials preclude any firm recommendations regarding the benefit of this antiproliferative agent for restenosis. Further trials are still

150 required, and attention will need to be directed to optimization of dosing regimen, accurate methods of measurement, and further understanding the complex relationship between angiographic dimensions and clinical outcomes.

Inhibitors of the Early Coagulation Cascade Several studies have shown the stimulatory effects of coagulation cascade proteins in the process of smooth muscle cell proliferation in vitro. 124-t26 Thrombin ts a recognized mitogen for smooth muscle cells, 124,126as well as a trigger for release of PDGF 127 and other growth factors from smooth muscle and other cells. 128 The early coagulation proteins such as activated factor X (factor Xa) also appear to have direct proliferative actions. L25 Although high doses of the thrombin inhibitor hirudin have been found to inhibit restenosis m an animal model. 129-13° the high incidence of bleeding complications suggests a narrow therapeutic windoW for these d r u g s J 31,132 In contrast, inhibitors of early Coagulation cascade proteins such as the factor Xa inhibitor tick anticoagulant peptide appear to be associated with a lower incidence o f bleeding while still effectively preventing restenosis. In an interesting study, Jang et al assessed the comparative effects of blockade of the coagulation cascade at various levels on neointimal hyperplasia m a rabbit atherosclerotic vascular injury model. 133 Two agents that inhibited the tissue factor-factor VIIa complex reduced the amount of neointimal hyperplasia, whereas agents that inhibited proteins lower down in the coagulation cascade (factor Xa and thrombin) were ineffective. The investigators conduded that proximal extrinsic pathway inhibition was more potent than inhibition of factor Xa or thrombin at preventing neointimal hyperplasia. Even though these agents remain virtually untested in human beings to date, these data suggest an exciting new avenue of investigation for the prevention of restenosis.

Calcium Channel Antagonists Calcium channel antagonists have built up a traditional role as an almost routine therapy in the postangioplasty patient. Although this pra crice may have a more empirical than scientific qrigin! there are data that these drugs can suppress neointimal proliferation TM as well as inhibit

LEFKOVITS AND TOPOL

platelet aggregation3 35 Five clinical trials have been performed with calcium antagonists. 136-140 Individually, the results of these trials have been unconvincing. Differences in trial design and definition of endpoints as well as small sample sizes make comparisons among the trials difficult. However, a meta-analysis of these trials was performed and showed an approximately 30% reduction in the odds of angiographic restenosis compared with control. ~4~ Despite limitations such as withdrawal bias and incomplete a>aiographic follow-up, these data suggest a possible future role for calcium antagonists in restem;sis. Larger clinical trials are clearly warranted, and the issue of the relative safety of the dihydropyridines must be determined before the widespread use of these agents can be recommended.

Nitric Oxide Donors Perhaps one of the most exciting recent developments in the understanding and treatment of restenosis centers around nitric oxide (NO) and its role in endothelial function and the vascular response to injury. 142 NO is now recognized as a principal component for the maintenance of vascular tone through its endothelium-dependent vasodilatory actions. 143-145 It also appears to have an important role in the response to vascular injury. Early responses such as platelet aggregation146a47 and leucocyte adhesion >s are inhibited by NO. NO has also been found to inhibit smooth muscle cell proliferation 149 and may even have cytotoxic effects on vascular smooth muscle cells in high concentration.15° These muhiple effects of NO on vessel response to injury make it a logical and potentially powerful agent to control the process of restenosis. A number of strategies have already been tested to deliver NO m the site of inju W. Systemic delivery of NO-donating molecules such as nitroglycerin and nitroprusside has met with limited success, mainly because of their short half lives, although administration of spontaneous NO donors has been more promising.t51,152 Early reports of local delivery of NO donors at the site of injury have also yielded encouraging resultsJ 53,154Gene therapy has been used to induce expression of NO synthase in vascular smooth muscle cells. Von Der Leyen et al were able to transfect ballooninjured rat carotid vascular smooth muscle cells

PHARMACOLOGICAL APPROACHES TO RESTENOSIS

with endothelial cell NO synthase, resulting in elevated NO production, normalized vasorelaxation, and inhibition of neointima formation. 155 Experience with NO donors in human beings is still limited. Langford et al administered a NO donor into the coronary arteries of six patients undergoing coronary angioplasty, resulting in significant antiplatelet effects including reduced expression of platelet surface P-selectin and glycoprotein IIb/IIIa receptor. 156 A preliminary report from the ACCORD study, a muhicenter study evaluating systemic administration of NO donors after coronary angioplasty, reported significant improvements in angiographic restenosis.157 These data, although preliminary, do suggest at least a modest benefit on restenosis. Further studies with enhanced techniques of delivery and larger numbers of patients will further help to determine whether NO therapy will emerge as a potentially useful tool for preventing restenosis.

Limitations of Drug Trials It is clear from the previous discussion that tremendous effort has already been focused on pharmacological treatment for the prevention of restenosis. There remains the overriding question of why so many drugs that show efficacy in vitro or in experimental studies fail when tested in human beings. In the search for more effective measures against restenosis, it may be worthwhile considering some of the possible explanations for these apparent discrepancies.

Applicability of Animal Models Not surprisingly, the failure of so many drugs that have otherwise been found effective in animal models of restenosis has raised serious questions regarding the overall validity of animal models in restenosis research. Although animal models in general have been used to assess changes in neointimal formation after arterial injury, models differ substantially among themselves. Differences arise in the size of animal, type of artery, type and degree of arterial injury, amount of mural thrombus formation, and release and action of species-specific growth factors. Moreover, there is always a degree of uncertainty regarding the translation of an effective dose in an animal model to an appropriate dose in human beings. This was well illustrated in the MARCATOR 6~and

151 MERCATOR63 trials, which evaluated cilazapril in the prevention of restenosis. Despite encouraging results with this agent in rat restenosis models, the two large-scale human trials failed to show any benefit. On a comparative basis, the dose used in the human studies was only a fraction of the dose used in the rat calculated on a milligramper-kilogram body weight basis. Yet, even at the dose used in human beings, a substantial proportion of the patients developed side effects, indicating that the drug was not likely to be tolerated at the dose levels found effective in the rat. Most animal models involve arteries that are otherwise free of atherosclerosis, unlike the human situation. The extent and depth of arterial injury may differ among the various animal models and in animals versus human beings. Methods of assessment (histopathological versus angiographic) may also account for some of the discrepancies. Perhaps most obviously, the results in one species may not be applicable across species types. There are certainly many examples of drugs that appear effective in one particular animal model but riot in others, and this lack of applicability may extend from animal models to human beingsJ 58 Finally, it has become increasingly recognized that restenosis involves multiple other processes apart from neointimal proliferation7 -4 Yet animal models tend to evaluate single pathological processes--mainly formation of neointima. Despite these problems, much has been learned from these models, and a unified hypothesis has been put forward that suggests that differences among animal models and their neointimal responses to injury can be predicted by the volume of mural thrombus formation. 158 Although there is no perfect animal model for human restenosis, their use has certainly enhanced our understanding of the mechanisms of the vascular response to injury. Despite their limitations, studies using animal models are likely to remain an important tool for the testing of future therapeutic strategies against restenosis.

Angiographic Restenosis: Its Definition and Clinical Utility In general, the field of restenosis research has been preoccupied with angiographic measurements of lumen dimensions. Alternative methods of assessment such as functional or clinical effects

152

LEFKOVITS AND TOPOL

RestenosisRate (%) P=n.s. I

4O

P=.01

P=.024

30 20

changes may have no bearing on patients' clinical outcomes, a phenomenon labeled clinical-angiographic dissociation3 59 Although it is rational to use absolute (angiographic) measures to assess results in experimental models of restenosis, it has been suggested that clinical evaluation of strategies aimed at reducing restenosis should incorporate both clinical and imaging criteria. 1,159

10

Okamoto et al n=90

Nishikawaet al n=137

Maresta et al 11=254

Fig 3. Restenosis rates from three clinical trials of trapidil, a competitive antagonist of the receptor for PDGF, for the prevention of restenosisY T M Although these trials involved small numbers of patients, promising reductions in restenosis were observed. [] Trapidil, [] Aspirin Control.

have received relatively little attention despite the distinct possibility of these parameters being more predictive of the patients' eventual outcomes. The predominant reliance on angiography tends to overshadow the fact that as an imaging technique, angiography has many limitations. 159 Visual assessment has been shown to be inaccurate and poorly reproducible. 16° Hand-held calipers and computerized edge detection algorithms have become the gold standard for the coronary stenoses. Yet a significant degree of variability remains even with these techniques. 161,162 Equally as important to the assessment of restenosis is the definition of restenosis used. Although restenosis is often thought of as an all-or-none response, it is clear that virtually all patients develop some renarrowing after angioplasty and that this process follows a Gaussian distribution. Definitions of restenosis differ substantially among the many restenosis trials, making comparison of results difficult. Although introduction of measurements such as acute gain and late loss have shifted the focus on restenosis to a continuous rather than a binary definition, percentage changes in luminal dimensions may not be as meaningful to the treating physician as the concept of a binary measure of the presence or absence of restenosis. Other problems such as proportional versus absolute measurements, the relevance of functional measurements such as translesional gradients, and doppler flow measurements cannot be overlooked. Perhaps most importantly, angiographic

The Future of Drug Prevention of Restenosis Despite the intensive research into the pharmacological control of restenosis, no systemic agent has been conclusively shown to reduce restenosis. It is however disappointing that the number of large-scale phase III trials being conducted has dropped off substantially over the last 5 years. Instead, the search for the breakthrough against restenosis has headed in many different directions. The use of intracoronary stents reviewed elsewhere in this issue appears to be a particularly important nonpharmacological advance in the prevention of restenosis. Novel approaches such as localized endovascular irradiation, new biological targets such as the o~v~3integrin, the restoration and maintenance of endothelial function, and the role of coagulation proteins and growth factors are all likely to shape the direction of future research into restenosis and its prevention. It is probably naive to think that the magic bullet will one day be discovered to cure restenosis. Nevertheless, several promising avenues are already apparent, and it is likely that the incidence of restenosis can be further improved through a multifaceted approach combining measures to control all the various elements that contribute to the process of renan'owing after coronary intervention.

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