Jeffrey L Anderson, MD, MACP, FACC, FAHA. Intermountain Medical Center, Murray, Utah University of Utah School of Medicine, Salt Lake City, UT

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1 Tegaserod: are the data sufficiently compelling for a class effect that CV safety outcomes should be required for all 5HT-4 agonists for severe constipation? Jeffrey L Anderson, MD, MACP, FACC, FAHA Intermountain Medical Center, Murray, Utah University of Utah School of Medicine, Salt Lake City, UT No current RWIs to disclose

2 Background Tegaserod, a selective serotonin-4 receptor agonist, is a first (and only) in-class drug, approved in July 2002 for short-term (4-12 weeks) treatment women with irritable bowel syndrome with constipation as their main symptom and in women <65 years old with severe, chronic constipation of unknown cause. Studies of tegaserod have identified no ECG effects, no CV effects, and no propensity to cause vascular spasm. In March 2007, FDA suspended its use, citing increased CV events in the clinical trials database (13 vs. 1 events in active vs. control patients). However, with no known mechanistic basis for an adverse CV effect of tegaserod, the question is raised as to whether the association was due to chance.

3 Proposed Cardiovascular Functional Effects of 5-HT Receptors Receptor (s) 5-HT1A 5-HT1B 5-HT1D 5-HT2A 5-HT3A/3B 5-HT4 5-HT7 5-HT-1E, -1F, -2C, -5A, -6 Tegaserod has high affinity for 5HT4 and moderate affinity for 5HT1 receptors Proposed Functional Effects Renal vascular dilation? Vasocontriction, cerebral arteriolar dilation Vascular nerve endings? Vasoconstriction, platelet aggregation Reflex bradycardia? Pain? Peristaltic stimulation & intestinal secretion; cardiostimulation, pulmonary venous dilation? Vascular relaxation? Unknown Modified, adapted after Pharmacol & Therapeut 2006; 11:674

4 Background (cont.) A March 30, 2007 press release from the sponsor stated: This action has been taken after Novartis notified the FDA about a retrospective analysis of data from more than 18,000 patients in the clinical trial database. A recent analysis of the entire clinical database revealed a statistically significant imbalance in the incidence of cardiovascular ischemic events in patients taking Zelnorm compared to those taking placebo. These events included myocardial infarction (MI), stroke, and unstable angina. The data showed that events occurred in 13 out of 11,614 Zelnorm-treated patients (0.11%) compared to 1 case in 7031 placebo-treated patients (0.01%). All patients affected had pre-existing CV disease and/or CV risk factors. The rate of cardiovascular ischemic events seen in Zelnorm-treated patients corresponds approximately with the expected rates for such events in the general population (i.e., about 5.5 per 1000 patientyears [pt-y] observed vs pt-y expected for women and pt-y expected for men).

5 Critical Database Review Presenter interest in this reported association was piqued after an independent review of an updated primary database by the presenter made the following observations among the 14 reported events: 3 events were not confirmed. 7 events were soft, chest pain ( anginal ) events, known to be highly unreliable for predicting a coronary syndrome, especially in young women. There was no temporal consistency between time of treatment and time of event. The difference in the balance of events, i.e., of hard events, 5 vs. 0 or 1 (depending on whether a TIA is counted as a hard event), is not significant (p= )

6 An Independent Assessment of the Safety of Tegaserod To independently assess the CV safety of tegaserod, patients in the Intermountain Healthcare e-database were identified as tegaserod-treated (n=2603) and matched 1:6 by age, sex, and date of tegaserod initiation to untreated patients (n=15,618) Age averaged / y, and 94% were female. Tegaserod was given for a mean of 126 days, median 60 days. Total follow-up averaged 2.5 years. Primary MACE endpoint: MI, stroke/tia, hospitalization for unstable angina, or CV death during f/u. Secondary endpoints: MACE events at 3 mo (during drug exposure); individual event rates; multivariable adjusted rates (adjusted for history of CV disease and CV risk factors). JL Anderson, et-al. JCVPT 2009; 4:170-5

7 Intermountain Tegaserod Study: Results During 2.5 average years of f/u, 66 incident CV events occurred (0.16% pt-y or 1.6/1000 pt-y) Event rates did not differ in Rx vs. control groups - 12 events/2603 tegaserod pts (0.45%) - 54 events/15,618 control pts (0.35%) - Unadjusted OR: 1.27 (95% CI, , p=0.46) - 9.0% of tegaserod and 4.1% of control patients had a CV risk factor at baseline. - CV events were more common with a pre-existing RF (2.4% vs 0.25%, p<0.001). - Adjusted OR: 1.06 (95% CI, , p=0.85) - Events occurring within 3 months: tegaserod=0 (0%), control=7 (0.04%), p=0.60

8 Individual Event Rates Event Total n (%) Tegaserod, n (%) Control n (%) P Value N subjects 18, ,618 Total events 66 (0.36%) 12 (0.46%) 54 (0.35%) 0.46 MI 13 (0.1%) 1 (0.04%) 12 (0.08%) 0.50 UA 2 1 (0.04%) 1 (0.01%) 0.16 CVA/TIA 46 10* (0.38%) 36 (0.23%) 0.16 CV death 6 0 (0.0%) 6 (0.04%) 0.35 *All at >3 mo JL Anderson, et-al. JCVPT 2009; 4:170-5

9 Intermountain Tegaserod Study: Conclusions CV event rates were very low (1-2/1000 pt-y) and similar to or lower than expected (3-5/1000 pt-y) in this population of mostly pre-menopausal women. TIA/CVA was the most common event, but event rate (0.1% per year) is lower than reported in the WHI Study (0.23% per year), who also were generally younger women (90% were <65 years old) at primary CV risk. CV events were much more likely to occur in those with baseline CV risk factors. CV risk was not increased with tegaserod treatment, both overall and at 3 months.

10 Confirmatory Epidemiological Study

11 No Evidence for Platelet Effects

12 The Challenge of Subgroup Analysis The interest is in relative, not absolute subgroup effects. The interest is in subgroups identifiable at the start of the study. Subgroup claims are only as credible as the studies from which they arise. Subgroup effects are not all-or-nothing decisions. X Sun, JPA Ioannidis, et-al. JAMA 2014; 311:405-11

13 Guidelines for Interpreting Subgroup Analyses: Can chance explain the subgroup differences? Is the subgroup difference consistent across studies? Was the subgroup difference one of a small number of a priori hypotheses in which the direction was accurately prespecified? Is there a strong preexisting biological rationale supporting the apparent subgroup effect? X Sun, JPA Ioannidis, et-al. JAMA 2014; 311:405-11

14 From: How to Use a Subgroup Analysis: Users Guide to the Medical Literature JAMA. 2014;311(4): doi: /jama P=0.003 for interaction by zodiac sign Figure Legend: Subgroup Analysis of the Second International Study of Infarct Survival Date of download: 2/10/2014 Copyright 2014 American Medical Association. All rights reserved.

15 Are Highly Selective 5HT4 Agonists Safer?

16 Potential Implications for Tegaserod and other 5HT4 Agonist Development 1) Scientific questions: 1) How much weight to put on retrospective subgroup analyses? 2) What is the potential mechanism (if any) of adverse effects? Arrhythmia, vasospasm not identified. Study of prothrombotic, platelet proaggregatory effects also negative. 2) Safety question: What additional safety data should be required of tegaserod or other 5HT4 agonists? Multiple epidemiological studies? These plus mechanistic studies? Large, prospective safety study (but recognizing the very low CV risk in the target population)? 3) Related safety question: Since events in the Novartis DB were restricted to those with known vascular disease or risk factors and were markedly increased (by 10-fold) with RF in the Intermountain study, could tegaserod be reintroduced for premenopausal women with IBS at low CV risk while awaiting further studies? 4) A more general question: What degree of tolerance for CV adverse risk should be allowed for drugs used to treat highly symptomatic but nonlethal conditions (i.e., what benefit/risk assurance is acceptable?)