M. Cortellaro: Professor of Internal Medicine, Milan University, Head of Medical Clinic L. Sacco Hospital, Milan M. Cambielli: Segretario Nazionale SNAMID, Milan

The June 10 issue of BMJ contained an editorial by J. Moon and R. Bogle (1) entitled “Switching statins”.

They noted first of all that the “statins are one of the great success stories of preventive medicine” and that “85% of all statin prescriptions in England are for simvastatin and atorvastatin … usually at low doses”. They comment that for long-term prevention (moderate doses) there is strong clinical evidence of the effectiveness of atorvastatin 10 mg in patients with hypertension and diabetes, as reported in ASCOT-LLA (2) and CARDS (3) trials, and of simvastatin 40 mg in patients at high CV risk or after myocardial infarction, in agreement with the HPS (4). The editorial claims that simvastatin 40 mg has the same lipid lowering effect as 10-20 mg atorvastatin. However, the trials cited - 3T (5), CURVES (6) and Stellar (7) - found atorvastatin superior to simvastatin in lowering LDL-C, and the meta-analysis by Law et al. (BMJ 2003) showed that atorvastatin 20 mg lowered LDL-C more than simvastatin 20 mg (8). Judging from the literature, therefore, the suggestion to replace atorvastatin 10-20 with simvastatin 40 might not be appropriate since clinical evidence points to the advantage of lowering cholesterol as far as possible (9-10). In addition, looking at the pharmacological properties and drug interactions this substitution might place patients at risk of side effects. The statins do not have the same interaction profiles and from a purely pragmatic viewpoint replacing atorvastatin with simvastatin might lead to problems that would not be immediately detectable with substances such as verapamil and warfarin (11). But how does the evidence lend itself to comparison ? The editorial mentions a meta-analysis by the authors, based on RCT using simvastatin 40 and atorvastatin 10, which found no difference between the two molecules as regards total mortality, fatal coronary disease or stroke. It is worth noting that in populations with stable IHD, clinical trials testing long-term statins, even at high doses, have not found any reduction in CV mortality considered alone; this might be because of the numbers of events. They did, however, find a reduction in fatal and non-fatal events cumulatively (12-13). A recent meta-analysis of RCT with placebo (14) comparing this evidence found that the risk of major coronary and major cerebrovascular events was reduced by respectively 28% and 24% in trials with simvastatin and 39% and 32% with atorvastatin. The evidence of equivalence, therefore, mentioned in the editorial – even in terms of outcomes – does not appear comparable, as the trials with atorvastatin 10 mg (ASCOT-LLA (15) and CARDS (16)) were in primary prevention, whereas those with simvastatin (4S and HPS) were for secondary prevention, except for 35% of the population enrolled in HPS. A meta-analysis of over 90,000 patients (17) treated with statins found a linear correlation between the reductions in LDL-C and events, and stressed that the real determinant of the efficacy of these drugs was the patient’s absolute risk. In assessing efficacy, therefore, we must very carefully evaluate the CV risk of the population in which a particular statin is tested. This implies that the studies with the two drugs mentioned in the editorial are not really comparable. Then there is also the question of the duration. Both CARDS and ASCOT-LLA had a shorter median follow-up than 4S and HPS (3.9 vs. 5 years) as they were stopped for ethical reasons. We have, however, to note that the effect, in terms of reduction of events, rises with the duration of treatment; according to Law’s meta-analysis (8) the risk reduction rises from 6% in the first and second years of treatment to 21% in the sixth year. Another important point is that while the HPS curves start to diverge at 18 months, in the CARDS trial they are already parting at 30 days, and the difference is significant at 18 months’ follow-up (18). There is also the fact that the subgroup with diabetes mellitus in the HPS was large, with higher cholesterol levels and greater CV risk, as the trial was designed to get a prompt result, which was demonstrated in CARDS. It therefore seems clear that combining various studies with differences in design, duration and types of patient tipologia is not really correct from the methodological point of view, and is an inappropriate basis for guidelines for clinical practice. The suggestion that one statin should automatically be used in place of another, on the basis of equivalence that has not really been demonstrated, is quite likely to be a source of harm to patients, requiring them to return to their previous therapy, but with the additional costs for seeking and correcting the damage. Last but not least there is the question whether this substitution is scientifically justified when the drugs involved are of the same class, with the same mechanism of action, but do not enjoy the same backing of evidence of benefit. REFERENCES 1. Moon JC, Bogle RG. Switching statins. BMJ 2006; 332(7554) : 1344-5 2. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361(9364) : 1149-58 3. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364(9435) : 685-96 4. Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361(9374) : 2005-16 5. Olsson AG, Eriksson M, Johnson O, Kjellstrom T, Lanke J, Larsen ML, et al. A 52-week, multicenter, randomized, parallel-group, double- blind, double-dummy study to assess the efficacy of atorvastatin and simvastatin in reaching low-density lipoprotein cholesterol and triglyceride targets: the treat-to-target (3T) study. Clin Ther 2003; 25(1) : 119-38 6. Raal FJ. A single-centre retrospective observational study to evaluate the change in total cholesterol and LDL cholesterol in hyperlipidaemic patients switched from atorvastatin to simvastatin. Cardiovasc J S Afr 2004; 15(3) : 118-23 7. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, Cain VA, Blasetto JW. STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol. 2003 Jul 15; 92(2) : 152-60 8. Law M R, Wald N J and Rudnicka A R. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ, Jun 2003; 326 : 1423 9. Cannon C P, Braunwald E, McCabe C, Rader D J, Rouleaua J L et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. NEJM 2004; 350 : 1495-1504 10. Deedwania P, Barter P, Carmena R, Fruchart J C, Grundy S M et al. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: analysis of the Treating to New Targets study. Lancet 2006; 368 : 919-928 11. Baxter K and Lee C R. Advice on reducing the risk of statin interaction. Prescriber 5 June, 2006; 35-43 12. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P et al. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. NEJM 2005; 352(14) : 1425-11435 13. Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, Tikkanen MJ et al. High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction. The IDEAL Study: A Randomized Controlled Trial. JAMA November 16, 2005; 294(19) : 2437-2445 14. Zhou Z. et al. Are statins created equal? Evidence from randomized trials of pravastatin, simvastatin and atorvastatin for cardiovascular disease prevention. Am Heart J. 2006; 151 : 273-81 15. Sever PS, Dahlöf B, Poulter N, Wedel H et al. for the ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm /ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003; 361 : 1149-58 16. Colhoun HM, Betteridge D, Durrington PN, Hitman GA, Neil HA, Livingstone J, Thomson MJ, Mackness MJ, Charlton-Menys V, Fuller JH. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre, randomisedplacebo-controlled trial. Lancet 2004; 364 : 685-96 17. Cholesterol Treatment Trialist (CTT) Collaborators. Efficacy and safety of cholesterol lowering treatment: prospective meta-analysis of data from 90056 partecipants in 14 randomized trials of statins. Lancet 2005; 366 : 1267-78 18. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS). Diabetologia 2005; 48(12) : 2482-5

 

Nello scompenso cardiaco i sartanici sono tutti uguali ?" 
Il testo è : " Da un lavoro canadese apparso il 27 aprile su Pharmacotherapy risulterebbe che i pazienti anziani trattati con sartanici ( irbesartan, valsartan, candesartan e losartan) per scompenso cardiaco, hanno tassi di sopravvivenza peggiori se in terapia con losartan rispetto agli altri. Questi risultati dimostrerebbero l'assenza di un effetto classe per gli ARB". 

 

L’uso degli inibitori della pompa protonica: sono tutti egualmente efficaci?
Marco Cambielli  Responsabile Area Farmaco Segretario Nazionale SNAMID

...Alcune Autorità regionali del tutto recentemente stanno facendo passare il concetto di equivalenza per farmaci aventi la stessa indicazione e appartenenti alla stessa classe terapeutica..."

Gli inibitori di pompa protonica,(PPI) esameprazolo, rabeprazolo, lansoprazolo, pantoprazolo e omeprazolo, secondo la recente nota  AIFA 2006-2007 numero 48, trovano indicazione d’uso a carico del SSN per le indicazioni: ulcera duodenale o gastrica Hp positiva, ulcera duodenale o gastrica Hp negativa, malattia da reflusso gastro-esofageo con o senza esofagite, sindrome di Zollinger Ellison.

Alcune Autorità regionali del tutto recentemente stanno facendo passare il concetto di equivalenza per farmaci aventi la stessa indicazione e appartenenti alla stessa classe terapeutica. Se il concetto fosse valido, l’uso degli inibitori di pompa sarebbe intercambiabile e quindi troverebbe giustificazione la decisione di rimborsare per qualsiasi PPI prescritto solo il costo dell’unico generico o equivalente esistente , il lansoprazolo.

Con una ricerca condotta su PubMed ed Embase relativa alle pubblicazioni degli ultimi 5 anni abbiamo potuto documentare come effettivamente sia stata sostenuta la pari efficacia dei diversi inibitori di pompa nella eradicazione dell’HP (1,2,)

Tuttavia è stato da molti rilevato che  nonostante i parametri farmacocinetici chiave siano sovrapponibili, esistono differenze nel metabolismo epatico di questi farmaci che possono produrre una variabilità interindividuale della soppressione acida, della potenziale interazione tra farmaci e , quindi della efficacia clinica. Il dato più importante consiste nel polimorfismo genetico del citocromo P450, isoenzima 2C19, in grado di modificare il metabolismo di tutti i PPI, ma non del rabeprazolo. Inoltre il rabeprazolo ed il pantoprazolo hanno i minori rischi di interazioni farmacologiche, un dato fondamentale per trattare senza rischi categorie di pazienti che prendono altri farmaci; ad esempio con gli altri PPIs deve essere controllata la co-somministrazione  della  digossina ( aumentato assorbimento), ketoconazolo ( ridotto assorbimento), benzodiazepine(rallentato metabolismo e clearance), carbamazepina e ciclosporina(alterazioni del metabolismo dei farmaci che è inibito), indinavir (riduzione dell’assorbimento), warfarin (riduzione del metabolismo), olanzapina (aumento della clearance dell’olanzapina, metotrexate(blocco della secrezione tubulare del metotrexato). Problemi di interazioni esistono anche con teofillina, fenitoina e tacrolimus (3).

Il diverso stato di metabolizzatore  in base al polimorfismo del CYP2C19 ( metabolizzatori estensivi e metabolizzatori scarsi) condiziona le risposte al trattamento sia nel caso della eradicazione dell’Hp, che delle guarigioni dell’ulcera peptica, che della GERD (4) (5). In questo senso pantoprazolo e rabeprazolo differiscono dagli altri PPIs e quindi anche dal lansoprazolo. (6)

Ma anche il tipo di patologia da trattare condiziona le percentuali di guarigioni ottenibili coi diversi PPIs: si veda il caso delle esofagiti da reflusso. In una recente meta-analisi (7) viene accertato che le percentuali di guarigione dei trattati con esomeprazolo 40 mg rispetto ai trattati con dosi standard di altri PPIs ( tranne rabeprazolo per il quale non ci sono confronti) sono statisticamente superiori. La meta-analisi, condotta da impiegati dell’AstraZeneca, è comunque stata condotta con metodiche rigorose. Il dato è confermato da un’altra meta-analisi indipendente (8) L’esomeprazolo  determina una riduzione assoluta del rischio del 4% e un NNT di 25 rispetto ai PPIs di confronto e l’effetto si vede soprattutto nei casi più severi.

Anche in studi con confronti diretti in pazienti affetti da esofagite da reflusso,  l’esomeprazolo  risulta più efficace del lansoprazolo sia nella guarigione della patologia che nella terapia di mantenimento (9) (10)

La differenza di esomeprazolo versus pantoprazolo nel trattamento della esofagite  da reflusso non è   rilevante o meno rilevante in altri studi di confronto diretto. Ma questo esula dall’obiettivo di questa breve rassegna.

In conclusione  i PPIs non sono tutti uguali ed ogni medico deve poter decidere, secondo scienza e coscienza  ed avendo valutato la patologia ed il paziente da trattare, quale PPI scegliere, senza penalizzare su base economica i pazienti. Le decisioni adottate da alcune Regioni non si basano su dati scientifici, ma su criteri di opportunità economica.

• Bibliografia

• Gisbert JP Potent gastric acid inhibition in HP eradication Drugs 2005; 65 Suppl 1 83-96

• Keum B and coll Comparison of Hp eradication rate according to different PPI-based triple therapy. Korean J Gastroenterol 2005; 46(6); 433-9

• Robinson M , Horn J Clinical pharmacology of proton pump inhibitors: what the practising physician needs to know. Drugs 2003, 63(24): 2739-54

• Klotz U Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem Int j Clin Pharmacol Ther 2006; 44(7), 297-302

• Padol S and coll The effect of CYP2C19 polymorphism on H pylori eradication rate in dual and triple first line PPI therapies: a meta-analysis Am J Gastroenterol 2006; 101(7); 1476-8

• Gawronska-Szklarz B and coll Effect of CYP2C19 and MDR1 polymorphism on cure rate in patients with acid-related disorders with Hp infection. Eur J Clin Pharmacol 2005; 61(5-6) 375-9

• Edwards SJ and coll Systematic review: PPIs for the healing of reflux esophagitis- a comparison of esomeprazole with other PPIs  Alimen Pharmacol Ther 2006; 24(5): 743-50

• Gralnek IM and coll  Esomeprazole versus other PPIs in erosive esophagitis: a meta-analysis of RTCs  Clin Gastroenterol Hepatol 2006; 4;(12); 1452-8

• Devault KR Maintenace of healed erosive esophagitis: a randomised six-month comparison of esomeprazole 20 mg with lansoprazole 15 mg. Clin Gastroenterol Hepatol 2006; 4(7), 852-9

• Castell DO Esomeprazole 40 mg compared with lansoprazole 30 mg in the treatment of erosive esophagitis. Am J Gastroenterol 2002; 97(3); 575-83

Lo studio MEDAL - Un commento di Marco Cambielli"