NSAIDs, Myocardial infarction, rebound effect and similitude

Sir,

In the last issue of Homeopathy, I published a paper in which the evidence of the similitude principle in the light of fatal iatrogenic events of modern medicines was discussed in relation to the rebound effect or paradoxical reaction of the organism (secondary action or vital reaction of the homeopathic model).[ ¹ ] I mentioned some work on nonsteroidal anti-inflammatory drugs (NSAIDs) and increased the risk of acute myocardial infarction (AMI) after interruption of treatment.[ ^2,3 ] These reflect the results of experimental studies in which NSAIDs stimulate rebound platelet adhesion and thrombin activity.[ ^4,5 ]

Very recently McGettigan and Henry have published a systematic review of 23 observational studies (17 case–control and 6 cohort studies) of the effects NSAIDs, both non-selective and selective inhibitors of cyclooxygenase 2, on cardiovascular events in a population of 1.6 million of patients.[ ⁶ ] A dose-related risk was evident with rofecoxib, relative risk (RR) with 25 mg/day or less, 1.33 (95% confidence interval [CI], 1.00–1.79; 6 studies) and 2.19 (95% CI, 1.64–2.91; 7 studies) with more than 25 mg/day. Among the older, nonselective drugs, diclofenac had the highest risk with an RR of 1.40 (95% CI, 1.16–1.70; 9 studies), meloxicam RR 1.25 (95% CI, 1.00–1.55; 3 studies) and indometacin RR 1.30 (95% CI, 1.07–1.60; 6 studies). The data indicate that the risk increases early in treatment (first 30 days) and on first cardiovascular events.

In recent case–control study (33 309 cases; 138 949 controls) of the risks of hospitalisation with myocardial infarction and use of NSAIDs,[ ⁷ ] the RR estimates are: rofecoxib, 1.36 (95% CI, 1.18–1.58; 12 studies); diclofenac, 1.40 (95% CI, 1.19–1.65; 10 studies); meloxicam, 1.24 (95% CI, 1.06–1.45; 4 studies); indometacin, 1.36 (95% CI, 1.15–1.61; 7 studies). In another meta-analysis, Kearney et al studied the effects of selective and nonselective NSAIDs on the risk of serious vascular events for a period of at least 4 weeks duration (145 373 participants), reviewing data from 138 randomised trials and estimated a RR for rofecoxib of 1.42 (95% CI, 1.13–1.78) and for diclofenac of 1.63 (95% CI, 1.12–2.37).[ ⁵ ]

In elaborating a pathophysiological hypothesis for these cardiovascular events, I highlighted certain points: the events tend to occur after a short period of treatment (<30 days); are dose-dependent and often serious; they do not depend on a previous cardiovascular disease (first cardiovascular events). Studies of rebound effects or paradoxical reaction of the organism have found similar characteristics:[ ^8–11 ] the symptoms are of larger intensity than those initially suppressed; the reaction is fast, within 30 days after the suspension of the medicine (related to the half-life of the drug); the effect is proportional to the intensity of the initial contrary action (dose-dependent); the rebound effect is idiosyncratic, unrelated to previous disease or risk factors.

The precise mechanisms by which NSAIDs including COX-2 inhibitors increase cardiovascular risk are not clear: reduced prostacyclin production in the vascular endothelium, suppression of nitric oxide synthesis, diminished neovascularization, abolition of adrenomedullin activity, and increased free-radical production have all been implicated. Platelets play a pivotal role in the development of these cardiovascular events, and all these mechanisms also affect platelet activity.

Linking the rebound effect and platelet activity and considering that antiplatelet therapy with aspirin is associated with reduced vascular mortality, Serebruany et al [ ¹² ] sought to determine the effect of use and withdrawal of NSAIDs on platelet activity. Platelet characteristics from 34 aspirin-naive volunteers who were receiving unselective NSAIDs or selective COX-2 inhibitors were compared with 138 drug-free controls. Platelets were assessed twice at baseline (at least 1 month of treatment) and after a 14-day washout. Platelet activity during treatment was similar and unremarkable between groups. However, there was a highly significant increase of platelet activity after withdrawal of nonselective NSAIDs and selective COX-2 inhibitors. The authors concluded that drug cessation, rather than continuous therapy with these drugs, may be associated with rebound platelet activation, which may predispose to a higher risk of vascular events. Suspension of ibuprofen and other antiplatelet agents can also provoke rebound increase of platelet aggregation, with increased thrombus formation and cardiovascular events (AMI).[ ^13,14 ]

If the similitude principle is a ‘natural law’, whose expression is modulated by individual idiosyncrasy (individualisation), the occurrence of serious iatrogenic events after withdrawal of enantiopathic drugs demonstrates the importance of the rebound effect (paradoxical reaction or homeopathic vital reaction) in promoting deep alterations in the organic balance. Homeopathy turns this effect on its head, using it to therapeutic advantage.

• References

• 1 Teixeira M.Z. Evidence of the principle of similitude in modern fatal iatrogenic events. Homeopathy 2006; 95 (04) 229-236.
• 2 Fischer L.M., Schlienger R.G., Matter C.M., Jick H., Meier C.R. Discontinuation of nonsteroidal anti-inflammatory drugs is associated with an increased risk of acute myocardial infarction. Arch Intern Med 2004; 164: 2472-2476.
• 3 Kearney P.M., Baigent C., Godwin J., Halls H., Emberson J.R., Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006; 332 (75/53) 1302-1308.
• 4 Andrioli G., Lussignoli S., Ortolani R., Minuz P., Vella F., Bellavite P. Dual effects of diclofenac on human platelet adhesion in vitro. Blood Coagul Fibrinolysis 1996; 7 (02) 153-156.
• 5 Andrioli G., Lussignoli S., Gaino S., Benoni G., Bellavite P. Study on paradoxical effects of NSAIDs on platelet activation. Inflammation 1997; 21 (05) 519-530.
• 6 McGettingan P., Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006; 296 (13) 1633-1644.
• 7 Helin-Salmivaara A., Virtanen A., Vesalainen R. et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland. Eur Heart J 2006; 27 (14) 1657-1663.
• 8 Dayneka N.L., Garg V., Jusko W.J. Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm 1993; 21 (04) 457-478.
• 9 Krzyzanski W., Jusko W.J. Mathematical formalism for the properties of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm 1997; 25 (01) 107-123.
• 10 Sharma A., Ebling W.F., Jusko W.J. Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena. J Pharm Sci 1998; 87 (12) 1577-1584.
• 11 Hazra A., Krzyzanski W., Jusko W.J. Mathematical assessment of properties of precursor-dependent indirect pharmacodynamic response models. J Pharmacokinet Pharmacodyn 2006; 33 (06) 683-717.
• 12 Serebruany V.L., Malinin A.I., Bhatt D.L. Paradoxical rebound platelet activation after painkillers cessation: missing risk for vascular events?. Am J Med 2006; 119 (08) 707.e11–6
• 13 Goldenberg N.A., Jacobson L., Manco-Johnson M.J. Brief communication: duration of platelet dysfunction after a 7-day course of Ibuprofen. Ann Intern Med 2005; 142 (07) 506-509.
• 14 Collet J.P., Montalescot G., Blanchet B. et al. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 2004; 110 (16) 2361-2367.