The co-packaged product of pravastatin/aspirin was previously reviewed and was presented to the Cardio-Renal Advisory Committee on 18 January 2002. The advisory committee raised two objections to approval. The first was that not all doses were available in combination. In response to this objection, new formulations containing either 325 or 81 mg of aspirin will be available either with 20, 40 or 80 mg of pravastatin.

The second objection was a concern that aspirin as part of a co-packaged product, would inappropriately be continued or conversely, that the HMG CoA reductase inhibitor would be inappropriately discontinued at the time of a surgical procedure. This review consists of a summary and analysis of five publications that were submitted to the NDA on March 13, 2002. These publications are the sponsorís response to these concerns.

Publication #1

Heeschen C, Hamm CW, Laufs U, Snapinn S, Bohm M, White HD: Withdrawal of statins increases event rate in patients with acute coronary syndromes. Circulation; 2002; 105:1446-1452.

This was an observational study in a cohort of subjects who were enrolled in the PRISM study. These subjects had data available as to statin use at the time of entry and through the hospitalization. With respect to the PRISM study, a total of 3,232 subjects, who had evidence of unstable angina within 24 hours of study entry, received aspirin and were then randomized to additional therapy with tirofiban or heparin. The primary end point of the study was death, myocardial infarction or recurrent ischemia at each of the following time points 48-hours, 7-days and 30-days.

Of those enrolled into the PRISM study, 1,616 (50%) subjects had data available with respect to their statin use both pre-randomization as well as in-hospital. Of these subjects, 1,151 and 465 were not treated with or received statins at baseline, respectively. Of those treated with statins at baseline, 379 subjects continued statin use during hospitalization and 86 did not continue statin use. The comparison in this analysis is among those subjects whose statin usage was continued and those for whom it was discontinued.

The baseline characteristics, medical conditions and treatments did not differ in comparing those who continued and those who were discontinued from statins (data not shown here). The outcomes are shown in Table 1.

Table 1- Outcomes among those who had different statin status during the PRISM study

 

No Statins

N=1151

Statins continued

N=369

Statins Discontinued

N=86

P-value

Statins at baseline

N=465*

48 Hours:

Combined end point

Refractory ischemia

Death, MI

Death

MI

Revascularization

68 (5.9%)

51 (4.4%)

19 (1.7%)

3 (0.3%)

16 (1.4%)

6 (0.5%)

10 (2.6%)

12 (3.2%)

2 (0.5%)

0

2 (0.5%)

3 (0.8%)

9 (10.5%)

7 (8.1%)

4 (4.7%)

0

4 (4.7%)

1 (1.1%)

0.009

0.032

0.21

0.97

0.06

0.9

19 (4.1%)

19 (4.1%)

6 (1.3%)

0

6 (1.3%)

4 (0.9%)

7-Days:

Combined end point

Refractory ischemia

Death, MI

Death

MI

Revascularization

139 (12.1%)

122 (10.6%)

61 (5.3%)

25 (2.2%)

36 (3.1%)

235 (20.4%)

36 (8.5%)

26 (6.9%)

7 (1.9%)

2 (0.5%)

5 (1.6%)

64 (17.3%)

13 (15.1%)

12 (13.9%)

8 (9.3%)

1 (1.2%)

7 (8.1%)

22 (25.6%)

0.25

0.16

0.006

0.58

0.010

0.002

49 (10.5%)

39 (8.2%)

15 (3.2%)

3 (1%)

12 (2.6%)

86 (18.5%)

30-Days:

Combined end point

Refractory ischemia

Death, MI

Death

MI

165 (14.3%)

125 (10.9%)

86 (7.5%)

40 (3.5%)

46 (3.5%)

38 (10.0%)

30 (7.9%)

14 (3.7%)

6 (1.6%)

8 (2.1%)

15 (17.4%)

13 (15.1%)

12 (14.0%)

1 (1.2%)

11 (12.8%)

0.07

0.22

0.004

0.31

0.012

53 (11.4%)

43 (9.2%)

26 (5.6%)

7 (1.5%)

19 (4.1%)

p-values are derived from ANOVA.

*The statin at baseline group was added by this reviewer and was not included in the sponsorís calculations of p-Values.

The authors note that the outcomes among those that had their statins stopped were worse than among the subjects who had their statins continued during hospitalization. In particular, the combined end-point as well as death at 48-hours was worse than the cohort who discontinued statins when compared to the other cohorts.

(Comment: Considering those who were treated with statins at baseline (n=465), there did not appear to be a difference in outcome when compared to the no statin group (n=1151). Further subdividing the cohort into those in whom statin use was continued or discontinued must be viewed somewhat suspiciously. The cohort was not a randomized subgroup and the reason statins were discontinued is unclear. It is possible that those who were discontinued from statins were much sicker or rapidly deteriorated at baseline. They may have been made NPO because of their status during the first day of admission and therefore not given oral medication. In summary, this reviewer cannot differentiate whether the worst outcome was due to the cessation of therapy, or whether the cessation of statin therapy was due to the worsened status. In summary, this reviewer does not find this paper useful in deciding whether the short-term discontinuation of statin use is harmful).

Conclusion: This study result does not strongly support the contention that short term discontinuation of statin therapy has an acute effect on cardiovascular outcomes.

Publication # 2

Smith MS, Muir H, Hall R: Perioperative management of drug therapy, clinical considerations. Drugs; 1996; 51: (2) 238-259.

This publication reviews the available data on perioperative medication use. The publication does not supply any new data, but is a compendium of previous studies. These studies often rely on a surrogate marker or a very narrow population to ascertain whether the individual treatment should be discontinued or stopped at the time of a planned procedure. The treatments that were considered in the article were:

Antihypertensive medications (i.e. beta-adrenoreceptor blockers, alpha2-adrenoreceptor agonists, calcium antagonists, ACE inhibitors) and antiarrhythmic agents.

CNS agents: including therapies for affective disorders (MAO inhibitors, tricyclic antidepressants and lithium); anti-psychotics, anxiolytics, anti-epileptics and drugs for the treatment of Parkinsonís disease.

Drugs affecting the coagulation system: anticoagulants (e.g. heparin and warfarin), aspirin and non-steroidal anti-inflammatory drugs as well as thrombolytic agents

Glucocorticoids:

Aspirin:

The particular relevance of the publication is to the decision to continue aspirin during the perioperative period. The publication is a compendium of previously published studies, with no new investigations by the authors. The first issue broached in this section is the utility of a bleeding time test for defining the risk of hemorrhage during surgery. This issue is of minimal relevance to the issue at hand.

The largest source of data is the randomized data derived from the CLASP study (Collaborative Low-dose Aspirin Study in Pregnancy). The study was designed to determine if low dose aspirin (60 mg daily), relative to placebo alters the development of pre-eclampsia among pregnant women. (Note: this dose is lower than the proposed dose to be included in the combination product). The charts of 1,069 women who received epidural anesthesia were examined for evidence of adverse events (de Swiet M et al.; B. J Anaesth 1992: 69: 109). (note: the decision to perform the epidural anesthesia was not a randomized decision but a consequence of events that occurred to these subjects post randomization).

The review of the charts found 56 adverse events. Three of these events were possible epidural hemorrhages. Two of these events were in the placebo-treated subjects and one in the aspirin treated subjects. (Note: the severity of these events was not described. Since the event rate of the epidural hemorrhage is dependent on the skill of the anesthesiologist to perform the epidural anesthesia, the event rate on and off aspirin would not be expected to differ. The safety issue would be the severity of the bleed. This information was not available.).

The publication also referred to both a retrospective study among patients who received regional anesthesia for general surgery (Horlocker TT et al., -Anesth Analg 1990; 70: 631-4) and a prospective study in the same population (Horlocker TT et al.; Anesth Analg 1995, 80: 303-9). In the retrospective study, the outcome of 1,013 subjects who had a regional block prior to orthopedic surgery was collected for episodes of epidural hematoma. Of these patients, 39% were receiving preoperatively NSAID or aspirin. The review found no incidence of hematoma formation. In the prospective study by the same authors 924 subjects undergoing similar anesthesia for similar orthopedic procedures in which approximately 40% received NSAID or aspirin were examined for epidural hematoma. Again, the publication notes no increase in epidural hematoma rates.

Another study (Owens et al.; Anesth Analg 1986: 65:120-7) found among 33 cases of spinal hematoma one event that might have been related to post-operative use of aspirin.

For use prior to a procedure involving epidural blockade, the authors recommend albeit without data.

"Where it can be safely done without compromising patientís cardiac status, aspirin should be discontinued prior to surgery to prevent the increased risk of bleeding"

(Comment: The data base does not deal with the issues of bleeding form the infusion sites, the number of transfusions extra required or other hemorrhagic events, dehiscence of wound, stroke, gastrointestinal bleeds etc).

Conclusion: The strength of data for either stopping or continuing aspirin is not strongly supported by data as derived from this publication.

 

Publication # 3

Nelipovitz DT, Bryson GL, Nichol G: The effect of perioperative aspirin therapy in peripheral vascular surgery: A decision analysis. Anesth Analg; 2001; 93:573-80.

This publication, using a decision tree approach, explores the relative benefit of discontinuing or continuing aspirin treatment in a population undergoing an infra-inguinal revascularization procedure. There are no randomized clinical studies that specifically address the benefit/disadvantage to continue or discontinue aspirin therapy at the time of the revascularization procedure.

The decision tree analyzed by the authors is shown below.

Figure 1-Decision tree


























Subjects could either receive aspirin or have aspirin discontinued at the time of surgery. Complications that are considered are myocardial infarction, thrombotic and hemorrhagic CVAs, and GI or incisional bleeds. The decision tree presumed that, for this analysis, aspirinís effect both positive and negative has completely dissipated. The frequency of these events and the resulting outcomes were derived from a series of publications culled from a MEDLINE search. The authors utilized two measures to quantify the results of a particular outcome. The first measure is the survival rates. The second is the utility value, the quantitative assessment of the subjectís quality of life as a consequence of the event.

The specific values and the sources of the value are shown in Table 2. The authorís included data from both randomized and cohort studies. Standardized life tables were used to assess survival after the perioperative period. Since there was no data in the literature, the authors assumed that the mortality risk from an incisional bleed was 5%. The results of the authorís analysis are shown in Table 3.

Table 2. Studies, their size and the population enrolled with event rate and mortality rates as well as the relative effect of aspirin and the 95% CI

Event

Study

Type

N=

Population

Event Rate

Mortality

Myocardial Infarction

Christeropherson et al.;1

Stuhmeier et al.;2

Bode et al.;3

Iloprost Bypass Group 4

Sarac et al.; 5

Ouyang et al.; 6

Mamode et al,; 7

Von Knorring and Lepantalo 8

Taylor et al.; 9

Cutler et al.; 10

Yeager et al.; 11

Model Value (weighted mean)

RCT

RCT

RCT

RCT

RCT

Cohort

Cohort

Cohort

Cohort

Cohort

Cohort

100

297

425

577

56

24

191

105

207

130

572

PVD surgery

Vascular Surgery

PVD surgery

PVD surgery

PVD surgery

PVD surgery

PVD surgery

PVD surgery

PVD surgery

PVD surgery

PVD surgery

4%

1.3 %

4.5 %

4.1 %

5.4 %

8.3 %

7.3 %

2.9 %

3.4 %

5.4 %

3.5 %

3.98 %

50%

50%

N/A

N/A

N/A

N/A

57%

66%

29%

71%

25%

41.9%

Thrombotic

CVA

Hart and Hindman 12

Iloprost Bypass Group 4

Barnes et al.; 13

Turnipseed et al.; 14

Kelley and Kovacs 15

Model Value (weighted mean)

Cohort

RCT

Cohort

Cohort

Cohort

125

577

125

160

171

PVD surgery

PVD surgery

PVD surgery

PVD surgery

CVA patients

N/A

0.97 %

1.6 %

3.1 %

N/A

1.46 %

17.0 %

N/A

N/A

N/A

20 %

18.7%

Hemorrhagic CVA

Anderson et al.; 16

Petty et al.; 17

Model Value (weighted mean)

Cohort

Cohort

492

339

CVA Patients

CVA Patients

N/A

N/A

0.3 %

46%

30%

35.4%

GI bleed

Shina et al.; 18

Peura et al.; 19

Model Value (weighted mean)

Retrospective

Cohort

309

1235

PVD surgery

GI bleeds

0.3

N/A

0.3%

N/A

2.1%

2.1%

Incisional Bleed

Clyne et al.; 20

Davies et al.;21

McCollum et al.;22

Model Value (weighted mean)

RCT

Cohort

RCT

70

138

263

PVD surgery

PVD surgery

PVD surgery

1.4 %

10.1 %

3.4 %

5.07%

N/A

N/A
N/A

N/A

Relative Risk of Aspirin

RR ASA

CI

Myocardial Infarction

He et al.; 23

ATC 24

Model Value (weighted mean)

Systematic Review

Systematic Review

55462

68698

AHD

AHD

0.68

0.68

0.68

0.62-0.74

N/A

Thrombotic CVA

He at al.; 23

ATC 24

Model Value (weighted mean)

Systematic Review

Systematic Review

55462

65941

AHD

AHD

0.82

0.72

0.77

0.73-0.92

N/A

Hemorrhagic CVA

He et al.; 23

Model Value (weighted mean)

Systematic Review

55462

AHD

1.84

1.84

1.24-2.74

GI Bleed

Peura et al.; 19

Kelly et al.; 25

Model Value (weighted mean)

Cohort

Case control

1235

1752

GI Bleeds

GI bleeds

2.76

2.3

2.53

2.03-3.74

1.3-4.3

Incisional Bleed

ATC 24

Model Value (weighted mean)

Systemic Review

3999

PVD surgery

1.52

1.52

N/A

RCT=Randomized clinical trial PVD=peripheral vascular disease CVA= cerebrovascular accident

1. Christopherson R, Beatie C, Frank SM et al.: Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery: Perioperative ischemia Randomized anesthesia Trial Study Group. Anesthesiology; 1993; l79: 422-34

2. Stuhmeier KD, Mainzer B, Cierpka J et al.,: Small oral dose of clonidine reduces the incidence of intraoperative myocardial ischemia in patients having vascular surgery. Anesthesiology 1996; 85 706-12

3. Bode RHJ, Lewis KP, Zarich SW et al.,: Cardiac outcome after peripheral vascular surgery comparison of general and regional anesthesia. Anesthesiology; 1996 84 : 3-13.

4. Effects of perioperative Iloprost on patency of femorodistal bypass grafts: The Iloprost Bypass International Study Group. Eur J Vas Endovasc Surg. 1996; 12: 363-71.

5. Sarac TP, Huber TS, Back MR et al.,: Warfarin improves the outome of infrainguinal vein bypass grafting at high risk for failure. J Vasc Surg, 1998, 28: 446-57.

6. Ouyang P, Gersenblith G, Furman WR et al.,: Frequency amnd significance of early postoperative silent ischemia in patients having peripheral vascualr surgery. Am J Cardiol 1989; 64: 1113-6.

7. Mamode N, Scott RN, McLaughlin SC et al.,: Progressive myocardial infarction in peripheral vascular surgery. BMJ 1996; 312: 1396-7.

8.Von Knorring J, Lepantalo M : Prediction of perioperative cardiac complications by electrocardiograpphic monitoring during treadmill exercise testing before peripheral vascular surgery. Surgery; 1986; 99: 610-3.

9. Taylor LMJ, Yeager RA, Moneta Gl et al.,: The incidence of perioperative myocardial infarction in gebneral vascular surgery. J Vasc Surg; 1992 15: 52-9.

10 .Cutler BS, Wheeler HB, Paraskos JA, Cardullo PA: Applicability and interpretation of electrocardiographic stress testing in patients with peripheral vascular disease. Am J Surg 1981; 141: 501-6.

11. Yeager RA, Moneta GL, Edwards JM et al.,: Late survival after perioperativemyocardail infarction complicating vascualr surgery, J Vasc Surg; 1994; 20 : 598-604.

12.. Hart R, Hindman B: Mechanisms of perioperative cerebral infarction. Stroke; 1982; 13: 766-73.

13. Barnes RW, Liebman PR, Marszalek PB et al.,: The natural history of asymptomatic carotid disease in patients undergoing cardiovascular surgery. Surgery; 1981; 90:1075-83

14. Turnipseed WD, Berkoff HA, Belzer FO: Postoperative stroke in cardiac and peripheral vascular disease. Ann Surg; 1980; 192:365-8.

15. Kelley RA and Kovacs AG: Mechanism of in-hospital cerebral ischemia. Stroke; 1986; 17: 430-3.

16.Anderson CS, Jamrozik KDm, Broad hurst RJ, Stewart-Wynne EG: Predicting survival for 1-yesr among different subtypes of stroke; results from the Perth community stroke study. Stroke; 1994; 25: 1935-44.

17. Petty GW, Brown RDJ, Whisant JP et al.,: Frequency of major complications of aspirin, warfarin and intravenous heparin for secondary stroke prevention: a population-based study. Ann Intern Med; 1999; 130:14-22.

18. Shina MJJ, Atrip RG, Healy DA, Thiele BL: Relative rusks of limb revascularization and amputation in the modern era. Cardiovascular Surg; 1994; 2: 754-9.

19. Peura DA, Lanza FL, Gostout CJ, Foutch PG: The Americal College of Gastroenterology Bleeding Registry preliminary findings. Am J Gastroenterol; 1997; 92: 924-8.

20 .Clyne CA, Archer TJ, Atuhaire LK et al.,: Random Control trial of a short course of aspirin and dipyridamole (Persantin) for femorodistal grafts." Br J Surg; 1987 ; 74: 246-8.

21. Davies AH, Pope I, Collin J, Morris PJ: Early reoperation after major vascular surgery: a four-year prospective analysis. Br J Surg; 1992; 79: 76-8.

22 . McCollum C, Alexander C, Kenchington G et al.,: Antiplatelet drugs in femoropopliteal bypasses: A multicenter trial.. J Vasc Surg; 1991; 13: 350-61

23. He J, Whelton PK, Vu B, Klag MJ: Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA; 1998; 280:1930-5.

24. Collaborative overview of randomized trials of antiplatelet therapy I. Prevention of death, myocardial infarction and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelt Trialistsí Collaboration [published erratum appears in BMJ 1994; 308: 1549]. BMJ; 1994; 308: 81: 106.

25 . Kelly JP, Kaufman DW, Jungeton JM et al.,: Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-cated or buffered product. Lancet; 1996: 348: 1413-6.

Table 3. Specific parameters used and outcomes.

Strategy

MI

Thrombotic

CVA

Hemorrhagic CVA

Gastric Bleed

Incisional Bleed

All adverse events

Mortality

Crude life expectancy (yr)

Quality Ėadjusted life expectancy (QALYs)

- ASA

4.61 %

1.69%

0.37%

0.35 %

5.88 %

12.9 %

2.78 %

14.83

14.72

+ ASA

2.71%

1.12%

0.59 %

0.76 %

7.71 %

12.89 %

2.05 %

14.89

14.79

Based on this analysis, the authors anticipate a decrease in morality of 0.73%. (2.78%-3.05%) at the time of the procedure.

The authors also performed a sensitivity analysis of the data. One or more of parameters was altered to determine the effect on the analyzed outcome. Based on the sensitivity analysis,. the utility value of continuing aspirin exceeds the risk of bleeding from continued aspirin use as long as the risk of a myocardial infarction is approximately ľ that of the risk of incissional bleed (all other parameters held constant).

(Comments: The authors who devised this decision-tree analysis were well aware of its short comings. Below are ome of the authors as well as some of the reviewerís assessment of the decision tree analysis.

In summary, the publication is of interest in its elegance. Its accuracy, however, is unknown. A proper randomized clinical study has not been performed. The relevance of the conclusion is in this reviewerís estimate, speculative.

 

Publication # 4

Spell NO: Stopping and restarting medications in the perioperative period. Medical Clinics of N Amer; 85; 5 1117-1128

This is a review article that discusses the need to discontinue certain treatments prior to surgery. With respect to aspirin, no additional studies or new information is supplied. Based on the concern for the possibility of serious sequelae during certain forms of surgery e.g., neurosurgical, opthalmological or vascular, cessation of aspirin therapy may be warranted. For cardiovascular surgeries a consensus is absent, "Öalthough it is likely that aspirin increases perioperative mortality, evidence of significant effects on morbidity and mortality is lacking".

Conclusion: This publication adds no additional information with respect to the risk of continuing aspirin during the perioperative period.


Publication # 5

Koch KT, Piek JJ, de Winter RAJ, Mulder K, Schorborgh CE, Tijssen GP, Lie KT: Two hour ambulation after coronary angioplasty and stenting with 6F guiding catheters and low dose heparin; Heart; 1999: 81 53:56

The purpose of the study described by the paper is to determine whether early ambulation (2 hours) after elective coronary angioplasty was safe. The study consisted of a 621 consecutive subjects treated at the Academic Medical Centre Mebergdreef, Amsterdam, Netherlands with elective angioplasty. Each of the procedures was performed using a 6F guiding catheter by the femoral approach with a standard dose of 5000 IU of heparin. Those patients given other anticoagulation were excluded from analysis. All patients were given aspirin at a dose of 100 mg/day. Patients who were stented also received ticlopidine at 250 mg daily. Haemostasis was applied by manual compression followed by the application of a manual compression bandage, after removal of the catheter sheath. Of the 621 subjects 300 patients were eligible for 2-hour ambulation. Five patients had bleeding complications at or immediately after ambulation (1.7%). A total of 9 subjects (including, one subject who had bleeding complications at ambulation). This result suggests that after low dose short-term aspirin regimens, excessive bleeding from the catheterization insertion site was not excessive.

 

 

 

Overall Analysis: The supplied publications are only marginally pertinent to the safety of the continued use of aspirin during the peri-operative period. A randomized, prospective study in discontinuing or continuing aspirin in a whole series of situations defining the benefit/risk relationship has not been performed. The decision tree analysis by Nelipovitz is elegant in thought but of unknown accuracy and unknown applicability to the vast majority of situations for which the decision to discontinue aspirin would be relevant. The other publications are compendiums of data with the individual studies not really "on point".