§ LIFT Study Early Termination: Analysis

• LIFT Tibolone Study Halted: Increased Risk of Stroke
  Evidencewatch reports an early termination of the Organon LIFT study investigating tibolone efficacy on new vertebral fractures in elderly osteoporotic women under DSMB and Steering Committee rules. The interim findings reported an increased incidence of ischemic plus hemorrhagic events (strokes) in tibolone treatment group compared to the control group.
  
  The precise and full clinical implications however are not wholly clear:
  
  
  1. The study population was elderly osteoporotic women with a high risk of fracture, with the average age at baseline (study entry - recruitment began in 2001, and recruitment completed June 2003) of 68. Yet the vast majority of tibolone users average 10 years younger given typical deployment for vasomotor (climacteric) hot flashes. Indeed, Evidencewatch notes that Organon scientists determined in 2004 that at least in the UK, tibolone was preferentially prescribed to women with an increased risk for breast and endometrial cancer (Wierik et al. Climacteric (2004): Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus study).
     
     
  2. The Organon Tibolone Clinical Study Database, comprised of more than 6500 women-years of tibolone use in women who are on average much younger than the elderly osteoporotic women included in the LIFT study, fails to suggest any significant increased risk of stroke.
     
     
  3. The study dose used in the LIFT study was 1.25 mg./daily, and indeed 1.25 mg also (as compared with 2.5 mg/daily) significantly decreases hot flashes, although the higher 2.5 mg tibolone dose is both faster in onset of action and with higher reductions in hot flash frequency and severity. However, it is important to note that the clinical trial database does not suggest that in younger postmenopausal women treated with either dose of tibolone, 2.5 mg nor 1.25 mg, there is any increased risk on stroke.
     
     
  4. It appears that the parameter with the most impact in the LIFT study's outcome regarding stroke is age, although this is also true for the placebo group. The fact that NO increases in incidence of VTE (venous thromboembolism) nor MI (myocardial infarction) are found with tibolone makes it more difficult to explain the mechanism by which tibolone increases the risk on stroke in these elderly women (I am indebted to Dr. Mirjam Mol-Arts, Livial Global Venture Teamleader and head of clinical projects in HRT at Organon, manufacturer of tibolone (Livial), for this clarification).
     
     Indeed, Evidencewatch notes that in our own research, some studies have found tibolone (2.5 mg/daily) to be safe in postmenopausal patients with high risk factors in their history such as thromboembolic disorders, diabetes mellitus, hypertension, cardiovascular disease, pulmonary embolism, and stroke (see F. Szanto, Tibolone therapy in postmenopausal women with a history of many risk factors) over a 36-month period, a finding hard to reconcile with the LIFT results.
     
     
  5. Against the thrust of the LIFT study findings on stroke, tibolone as a six-month course (at 2.5 mg/daily) in postmenopausal women was found to counteract the increase of the intima media thickness (IMT) of the common carotid arteries (CCA), as determined by Anedda et al. (Hormone Res (2004): Observational Study on the Efficacy of Tibolone in Counteracting Early Carotid Atherosclerotic Lesions in Postmenopausal Women) and also by Erenus et al. (Fertil Steril (2002): Effect of tibolone treatment on intima-media thickness and the resistive indices of the carotid arteries), and this suggests an anti-atherosclerotic effect by tibolone, as it is well-established that increased CCA-IMT values are associated with a higher risk of long-term stroke recurrence (Tsivgoulis et al., Stroke (2006): Common Carotid Artery Intima-Media Thickness and the Risk of Stroke Recurrence). [Tibolone's effect on CRP (C-reactive protein), also a risk factor for stroke, is not wholly clear, as there have been inconsistent findings across studies.]
     

§ Some Guidance on Stroke Risk Reduction

Evidencewatch continues to investigate this issue and will post additional guidance as appropriate, but pending that advises that women currently using tibolone explore this matter candidly with their physicians. Evidencewatch advises, however, for any women who elects to continue tibolone therapy that at the very least some basic proactive stroke-preventive measures be taken:

1. LD-Aspirin
   It is well-established that aspirin inhibits platelet aggregation by virtue of interfering with thromboxane synthesis (via irreversible acetylation of platelet cyclooxygenase), thus yielding clinical antithrombotic activity in which serum thromboxane levels (a marker of platelet activation) typically are reduced more than 95% even by low dosages (LD) of aspirin, defined as 75 - 162mg/daily (see the recent meta-analysis of Hennekens et al., J Cardiovasc Pharmacol Ther (2006): Dose of Aspirin in the Treatment and Prevention of Cardiovascular Disease: Current and Future Directions [pdf]; also the meta-analysis of all six major primary prevention trials by Jeffrey Berger and co-researchers, JAMA (Berger et al., JAMA (2006): Aspirin for the Primary Prevention of Cardiovascular Events in Women and Men - A Sex-Specific Meta-analysis of Randomized Controlled Trials). This translates to approximately a 24% reduction in the risk of ischemic stroke in women, and no significant change in hemorrhagic stroke risk (Ridker et al, New Engl J Med (2005): A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women). See also the AHA/ASA guidelines (Sacco et al., Circulation (2006): Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline) and Goldstein et al., Stroke (2006) [and also published in Circulation (2006)]: Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline)
   
   
2. Omega-3 Fatty Acids / Fish Oils
   Although early major epidemiological trial findings were not wholly consistent on the association of omega-3 fatty acids / fish oils and reduced risk of stroke (see the summary of trials <=2003 by Kris-Etherton et al., Arterioscler Thromb Vasc Biol (2003): Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease [AHA Scientific Statement]), the balance of the evidence to date favors a beneficial role. Thus the cross-sectional study of Hino et al. (Atherosclerosis (2004): Very long chain N-3 fatty acids intake and carotid atherosclerosis: an epidemiological study evaluated by ultrasonography) carotid ultrasonography to evaluate carotid intimal-medial thickness (IMT), a prognostic marker of stroke risk independent of the presence or absence of atherosclerotic plaque), finding that mean DHA (docosahexaenoic acid) intake was significantly and inversely related to IMT, suggesting that DHA consumption is protective against carotid atherosclerosis, and hence reductive of stroke risk (see also the review of the antiatherosclerotic and antithrombotic effects of omega-3 fatty acids: Robinson & Stone, Am J Cardiol (2006): Antiatherosclerotic and Antithrombotic Effects of Omega-3 Fatty Acids). In addition, fish oil appears to have a direct stabilizing effect on carotid plaque: Frank Thies and colleagues at the University of Southhampton (Thies et al., Lancet (2004): Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial) found that the n-3 PUFAs (polyunsaturated fatty acids) are incorporated into atherosclerotic plaques in such a way as to enhance plaque stability, as shown by the carotid plaque morphology with thicker fibrous caps, less inflammation, and fewer macrophages, suggesting that the increased stability of plaques induced by n-3 PUFAs may account for the observed reductions in non-fatal and fatal cardiovascular events associated with increased n-3 PUFA intake. More recently, Arja Erkkilä and co-researchers conducted a prospective cohort study (Erkkilä et al, J Lip Res (2006): Higher plasma docosahexaenoic acid is associated with reduced progression of coronary atherosclerosis in women with CAD) of postmenopausal women participating in ERA (the Estrogen Replacement and Atherosclerosis Trial) with established coronary artery disease (CAD) to assess the association between n-3 fatty acids in plasma lipids and the progression of coronary artery atherosclerosis, finding that women with higher plasma DHA exhibited less atherosclerosis progression, as expressed by decline in minimum coronary artery diameter or increase in percentage stenosis and had fewer new lesions; it is worthy to note that this beneficial association was restricted to DHA (and plasma phospholipid levels), as there was no significant association of atherosclerosis progression with either EPA (eicosapentaenoic acid) or ALA (alpha-linolenic acid).
   
   
3. Folate / Vitamins B6 and B12 (FOL-B Therapy)
   The questions of whether raised serum homocysteine concentrations are causally associated with ischemic heart disease and stroke and therefore also of whether folic acid in lowering homocysteine is reductive of ischemic stroke risk have generated considerable debate, but recent methodologically compelling reviews and meta-analyses are finally clarifying the intricate tangle of issues involved. It has been widely announced - mistakenly, as we suggest - that on these issues NORVIT, the Norwegian Vitamin Study (Bønaa et al., N Engl J Med (2006): Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction), and to a lesser extent the earlier VISP Trial (Toole et al, JAMA (2004): Lowering Homocysteine in Patients With Ischemic Stroke to Prevent Recurrent Stroke, Myocardial Infarction, and Death - The Vitamin Intervention for Stroke Prevention (VISP) Randomized Controlled Trial), was wholly dispositive, finding against FOL-B therapy (folate / Vitamin B6 /B12) reducing the risk of recurrent cardiovascular disease after acute myocardial infarction. And we note in passing that increased plasma homocysteine concentrations are associated with increased risk of cardiovascular morbidity, cardiovascular and noncardiovascular mortality, depression and, in the elderly, cognitive deficit, and among women in particular, raised homocysteine levels are associated with decreased BMD (bone mineral density) and increased risk of osteoporosis, as found by the Hordaland Homocysteine Study (HHS) among others (Refsum et al., J Nutr (2006): The Hordaland Homocysteine Study: A Community-Based Study of Homocysteine, Its Determinants, and Associations with Disease).
   
   However, our Evidencewatch review of these negative results finds them uncompelling: it is now apparent that the confounding factor is Vitamin B12, and that indeed the ability to absorb adequate levels of B12 is the key determinant of response to FOL-B therapy: so we now know that elderly patients with B12 levels <221 pmol/L require 1000 µg daily for adequate absorption and this likely entails administration of vitamin tablets at times other than mealtimes, when intrinsic factor is released from gastric mucosa (Rajan et al, J Am Geriatr Soc (2002): Response of Elevated Methylmalonic Acid to Three Dose Levels of Oral Cobalamin in Older Adults). Furthermore, a large proportion of vascular patients in these trials are the elderly in whom the key nutritional determinant of plasma homocysteine is vitamin B12, unfortunately with the well-known problem of malabsorption of B12, especially in an era of folate fortification (Robertson et al.,CMAJ (2005): Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products; see also Marc Fisher and colleagues (Fisher et al., Stroke (2005): Nutrition and Stroke Prevention) at the Stroke Prevention and Atherosclerosis Research Centre, Ontario who note that "the high prevalence of unrecognized deficiency of vitamin B12, requiring higher doses of vitamin B12 than have been used in clinical trials to date", a conclusion also shared by JD Spence (Stroke (2006): Homocysteine - Call Off the Funeral) who states from his own review that "It appears very likely that to achieve adequate reductions of tHcy in elderly patients, we will need higher doses of B12 than have been used in the past"; also the review of Andrès et al., CMAJ (2004): Vitamin B12 (cobalamin) deficiency in elderly patients).
   
   Others putatively negative findings are irrelevant, for example, the meta-analysis of the Tulane team of Lydia Bazzano and colleagues (Bazzano et al., JAMA (2006): Effect of Folic Acid Supplementation on Risk of Cardiovascular Diseases: A Meta-analysis of Randomized Controlled Trials), as they failed to recognized the critical importance of Vitamin B12, not just folate monotherapy, as priorly demonstrated by Robertson et al.,CMAJ (2005): Vitamin B12, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products, and of the confounding role of inadequate Vitamin B12 levels and/or utilizability, as we discussed immediately above (see also Quinlivan et al., Lancet (2002): Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease).
   
   Furthermore, another almost wholly unrecognized cofactor is betaine: betaine exhibits clear homocysteine-lowering activity (Ingeborg et al., Arch Int Med (2000): Betaine Supplementation and Plasma Homocysteine in Healthy Volunteers; Schwab et al., Am J Clin Nutr (2002): Betaine supplementation decreases plasma homocysteine concentrations but does not affect body weight, body composition, or resting energy expenditure in human subjects) and the same researchers more recently in Schwab et al., Am J Clin Nutr (2006): Orally Administered Betaine Has an Acute and Dose-Dependent Effect on Serum Betaine and Plasma Homocysteine Concentrations in Healthy Humans who determined that 3g and 6g daily doses of betaine, but not 1g, lowered plasma homocysteine concentrations for 24 hours), and this applies also to choline, supplemented as phosphatidylcholine, since Choline is the precursor for betaine (Olthof et al., Am J Clin Nutr (2005): Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men; also Cho et al., Am J Clin Nutr (2006): Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study). And the remethylation pathways used by both betaine and folic acid are interrelated, as shown by Melse-Boonstra et al (Am J Clin Nutr (2005): Betaine concentration as a determinant of fasting total homocysteine concentrations and the effect of folic acid supplementation on betaine concentrations) who demonstrated that folic acid supplementation increases betaine concentration, and Holm et al. (Arterioscler Thromb Vasc Biol (2005): Betaine and Folate Status as Cooperative Determinants of Plasma Homocysteine in Humans) who showed that plasma betaine is a strong determinant of increase in homocysteine after methionine loading, particularly in subjects with low folate status (see also Olthof et al., J Nutr (2003): Low Dose Betaine Supplementation Leads to Immediate and Long Term Lowering of Plasma Homocysteine in Healthy Men and Women) who determined that even doses of betaine in the range of dietary intake (approx. 0.5–2 g/daily) can substantially lower fasting plasma homocysteine. And Evidencewatch further notes another confounding factor: alcohol, at moderate (15 g/daily) or above, can modify the inverse association between folate intake and homocysteine, having as it does an adverse effect via increasing plasma homocysteine concentrations (Chiuve et al., Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma homocysteine).
   
   David Wald's team from the Wolfson Institute of Preventive Medicine, London, noting the conflicting findings on FOL-B therapy in the reduction of homocysteine levels have rendered an invaluable service in review the cumulative evidence across all study types, cohort, evidence from patients with homocystinuria, evidence from genetic polymorphism studies, and RCTs, concluding that taken together the evidence supports a modest protective effect of folic acid (Wald et al., BMJ (2006): Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence), even though this review may have underestimated the benefit given failure to control (1) dose of folate supplementation, (2) dose, and utilizability of Vitamin B12, and (3) issue of adequate betaine consumption.
   
   In sum, Evidencewatch finds on the balance of the evidence that (1) optimal FOL-B therapy - at least 2500 mcg of folic acid, 50 mg of vitamin B6, and 1000 mcg (1 mg) of vitamin B12 - is effective in significantly reducing plasma homocysteine levels, and (2) that increased plasma homocysteine levels are associated with adverse cardiovascular outcomes, including enhanced risk of stroke.
   
   
4. Cretan Mediterranean Diet
   The Cretan Mediterranean diet - the landmark Seven Countries Study found the diet of Crete to be associated with with the lowest rate of coronary heart disease and the longest life expectancy in examining the diets of the US, Italy, Japan, The Netherlands, Finland, the former Yugoslavia and Greece, and indeed the population of Crete had the lowest rates of cardiovascular disease and cancer - essentially a diet high in beneficial oils, especially olive and canola oil and fish oils, whole grains, fruits, and vegetables and low in cholesterol and animal fat, has been shown to reduce stroke and myocardial infarction by 60% in 4 years compared with the AHA diet (see, among man, Renaud et al., Am J Clin Nutr (1995): Cretan Mediterranean diet for prevention of coronary heart disease); see also the review of Artemis Simopoulos with the The Center for Genetics, Nutrition and Health (J Nutr (2001): The Mediterranean Diets: What Is So Special about the Diet of Greece? The Scientific Evidence), and the thoughtful commentary of J. David Spence (Circulation (2002): Importance of Diet in Vascular Prevention: Vastly Underestimated) how notes that these findings have been a more of neglect, especially surprising since the the cited cardiovascular benefit (including on stroke) is actually an effect twice that of the statin simvastatin (Zocor) in the Scandinavian Simvastatin Survival Study (see Spence's concluding injunction, with which we wholeheartedly (!) agree: "It is no longer reasonable for patients with vascular disease to be prescribed diets containing egg yolks and daily intake of animal flesh. Dietary recommendations need to take into account the importance of post-prandial fat and should be based on diets similar to the Cretan Mediterranean diet used in the Lyon Diet Heart Study"). And Evidencewatch notes that such a diet has many other benefits, including for example a reduced risk for the development of Alzheimer's Disease (Scarmeas et al, Arch Neurol (2006): Mediterranean Diet, Alzheimer Disease, and Vascular Mediation), and a recent systematic review has concluded that the Mediterranean Diet induces favorable effects on lipoprotein levels, endothelium vasodilatation, insulin resistance, metabolic syndrome, antioxidant capacity, myocardial and cardiovascular mortality, and cancer incidence in obese patients and in those with previous myocardial infarction (Serra-Majem et al, Nutr Rev (2006): Scientific Evidence of Interventions Using the Mediterranean Diet: A Systematic Review). See also Stehan Choi, CMAJ (2003): Benefits of Mediterranean diet affirmed, again), and Parikh et al, J Am Coll Cardiol (2005): Diets and Cardiovascular Disease: An Evidence-Based Assessment); also Anne Rosenfeld (Am J Crit Care (2006): State of the Heart: Building Science to Improve Women’s Cardiovascular Health). Patients on a Mediterranean Diet are evidenced to lose more weight, have lower C-reactive protein (CRP) levels, have less insulin resistance, have lower total cholesterol and triglyceride and higher HDL levels, and have a decreased prevalence of metabolic syndrome (Esposito et al, JAMA (2004): Effect of a Mediterranean-Style Diet on Endothelial Dysfunction and Markers of Vascular Inflammation in the Metabolic Syndrome - A Randomized Trial).
   
   
   
5. Addressing other Stroke Risk Factors
   And finally of course it should go without saying that all stroke risk factors should be explored and address aggressively in any comprehensive program of stroke risk reduction, including:
   
   
   • Overweight condition or frank Obesity
   • Hypertension
   • Diabetes / Metabolic Syndrome / Hyperinsulinemia
   • Lipid Disorders (especially elevated small LDL and lipoprotein(a)/lp(a))