Business Day

Study fails to close di­vide on statins

- MARIKA SBOROS

AMAJOR new Bri­tish study in the Lancet journal claims fi­nally to put to rest the ran­corous de­bate world­wide over the risk-ver­sus-ben­e­fit pro­file of statins. The au­thors say the ev­i­dence is “over­whelm­ing” that statins are safe and ef­fec­tive for pri­mary and sec­ondary pre­ven­tion — to pre­vent a first heart at­tack or stroke in oth­er­wise healthy peo­ple, or to pre­vent a sec­ond at­tack or stroke.

Statins are choles­terol-low­er­ing drugs used to treat or pre­vent heart dis­ease and stroke. They have be­come the world’s most pre­scribed drugs and gen­er­ate bil­lions in rev­enue for the drug com­pa­nies that make them.

The Lancet re­view is led by Rory Collins of Ox­ford Univer­sity’s clin­i­cal trial ser­vice unit. It has re­vived con­cerns about the se­ri­ous side ef­fects of statins that in­clude mus­cle, nerve, liver and car­dio­vas­cu­lar dam­age, en­docrine dis­rup­tion, erec­tile dys­func­tion and an in­creased risk of di­a­betes, cancer, cataracts and birth de­fects.

Top ex­perts world­wide say the new re­view is dan­ger­ous and mis­lead­ing be­cause it over­plays the ben­e­fits of statins for pri­mary pre­ven­tion and down­plays sig­nif­i­cant ev­i­dence of harm.

Collins and his co-au­thors say doc­tors and pa­tients have re­peat­edly un­der­es­ti­mated its ben­e­fits and ex­ag­ger­ated the harm. They say there has been “mis­in­ter­pre­ta­tion of the ev­i­dence”, in par­tic­u­lar a fail­ure to “ac­knowl­edge prop­erly the wealth of ev­i­dence from ran­domised con­trolled tri­als [the so-called gold­stan­dard of sci­en­tific tri­als], and the lim­i­ta­tions of other types of ob­ser­va­tional stud­ies”.

Their re­view cov­ers data over 30 years and has 300 ref­er­ences that in­clude ran­domised con­trolled tri­als.

The au­thors ex­plain how avail­able ev­i­dence on the ef­fi­cacy and safety of statin ther­apy should be in­ter­preted.

Collins says the re­view shows the num­bers of peo­ple who avoid heart at­tacks and strokes by tak­ing statin ther­apy are “very much larger than the num­bers who have side ef­fects with it”. Most side ef­fects can be re­versed with no resid­ual ef­fects by stop­ping the statin, he says.

The ef­fects of a heart at­tack or stroke not be­ing pre­vented are “ir­re­versible and can be dev­as­tat­ing”, he says.

“Con­se­quently, there is a se­ri­ous cost to pub­lic health from mak­ing mis­lead­ing claims about high side­ef­fect rates that in­ap­pro­pri­ately dis­suade peo­ple from tak­ing statin ther­apy de­spite the proven ben­e­fits,” Collins says. THE

au­thors con­clude that low­er­ing choles­terol by 2mmol a litre with an ef­fec­tive low-cost statin ther­apy (such as ator­vas­tatin 40mg daily, which costs about £2 per month in the UK) for five years in 10,000 pa­tients would:

Pre­vent ma­jor car­dio­vas­cu­lar “events” (heart at­tacks, is­chaemic strokes, coro­nary artery by­passes) in 1,000 peo­ple with pre-ex­ist­ing vas­cu­lar dis­ease (sec­ondary pre­ven­tion), and in 500 peo­ple who are at in­creased risk (due to their age or hav­ing hy­per­ten­sion or di­a­betes) but who have not yet had a “vas­cu­lar event” (pri­mary pre­ven­tion);

Cause five cases of my­opa­thy (mus­cle weak­ness, one of which might progress to the more se­vere con­di­tion of rhab­domy­ol­y­sis, if the statin is not stopped), five to 10 hae­m­or­rhagic strokes, 50-100 new

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cases of di­a­betes and up to 50-100 cases of symp­to­matic ad­verse events (such as mus­cle pain).

They say although fur­ther re­search may iden­tify small ad­di­tional ben­e­fi­cial or ad­verse ef­fects, this is un­likely “to ma­te­ri­ally al­ter the bal­ance of ben­e­fits and harms for pa­tients be­cause of the ev­i­dence gen­er­ated so far”.

Sun­ninghill car­di­ol­o­gist Jeff King says the Lancet re­view pro­vides “an ex­cel­lent, bal­anced ap­praisal of the cur­rent sta­tus ther­apy for pri­mary and sec­ondary car­dio­vas­cu­lar pro­tec­tion”. It fol­lows the lat­est Eu­ro­pean Car­di­ol­ogy So­ci­ety’s 2016 re­vi­sion of the lipid guide­lines pub­lished in the Eu­ro­pean Heart Journal in Au­gust.

Both pub­li­ca­tions “val­i­date and sub­stan­ti­ate” the re­sults of 30 years of med­i­cal re­search on the ben­e­fits of statins and the “ac­tual sig­nif­i­cance of side ef­fects”, King says. He is con­cerned about un­der­use of statins in SA, due in part to med­i­cal schemes’ trustees who do not gov­ern ad­min­is­tra­tors’ ad­her­ence to up-to-date ev­i­dence­based medicine with “proper cor­po­rate gov­er­nance and fidu­ciary re­spon­si­bil­i­ties”. Schemes rely on “out­dated lipid man­age­ment al­go­rithms” and poor re­im­burse­ment prac­tices, King says. An “un­eth­i­cal code of man­age­ment” has led to lower ther­a­peu­tic tar­gets, poorer out­comes, and higher hos­pi­tal­i­sa­tion and on­ward costs.

South African-born US lipi­dol­o­gist and car­di­ol­o­gist Den­nis Good­man says “the co­nun­drum for physi­cians re­mains: how low should we take LDL choles­terol”? By low­er­ing LDL choles­terol (low­den­sity lipopro­tein, so-called “bad choles­terol”), statin ther­apy has been “a corner­stone” of sec­ondary car­dio­vas­cu­lar dis­ease pre­ven­tion, says Good­man, clin­i­cal pro­fes­sor and di­rec­tor of in­te­gra­tive medicine at New York Univer­sity.

From 5% to 10% of pa­tients can­not tol­er­ate statins be­cause of mus­cle-re­lated ad­verse ef­fects.

New-gen­er­a­tion choles­terol­low­er­ing drugs, PCSK9 in­hibitors, are be­ing tested in large, phase-3 out­come stud­ies. They have demon­strated ex­cel­lent ef­fi­cacy (fur­ther 70% re­duc­tion of LDL choles­terol in ad­di­tion to statin ther­apy) and an ex­cel­lent short-term safety pro­file, he says.

In­di­ca­tions are for pa­tients with car­dio­vas­cu­lar dis­ease who are al­ready on max­i­mally tol­er­ated doses of statin and not at LDL goal, and pa­tients with the ge­netic con­di­tion, fa­mil­ial hy­per­lipi­demia. The re­sults are ex­pected next year. PCSK9

in­hibitors are “ex­pen­sive agents”, says Good­man. Out­comes data are likely to de­ter­mine whether the med­i­cal com­mu­nity and in­surance com­pa­nies “will em­brace or re­ject them”.

Sherif Sul­tan, pres­i­dent elect of the In­ter­na­tional So­ci­ety for Vas­cu­lar Surgery, is crit­i­cal of the Lancet pa­per. “It does not en­com­pass any sub­stan­tial new in­for­ma­tion or data and it lacks in­de­pen­dence,” says Sul­tan, pro­fes­sor of vas­cu­lar surgery at the Univer­sity of Ire­land.

“It is a re­view by the tri­al­lists who pub­lished all these data be­fore, with the long dec­la­ra­tion of in­ter­ests and whose re­search is paid gen­er­ously by the drug in­dus­try.”

The Ox­ford clin­i­cal tri­als unit re­ceives “hun­dreds of mil­lions of pounds of sup­port from the phar­ma­ceu­ti­cal in­dus­try”, he says.

Statins’ harm­ful­ness is “clear and data-driven”, says Sul­tan.

The au­thors have down­played their harm and do not make clear “when there is an ab­sence of ev­i­dence and ev­i­dence of ab­sence”.

Sev­eral in­de­pen­dent re­searchers have doc­u­mented that the num­ber of side ef­fects are much higher than the Lancet pa­per de­scribes, says Sul­tan. For ex­am­ple, the risk of my­opa­thy (mus­cle dam­age) is shown to be at least 10% to 20%, not 0.01% as de­scribed in the Lancet.

Mus­cu­lar side ef­fects are not “be­nign phe­nom­ena”, he says.

“They may have a dele­te­ri­ous ef­fect on el­derly peo­ple, be­cause the least ex­pen­sive and the least risky way to pre­vent heart dis­ease is reg­u­lar ex­er­cise.”

Sev­eral stud­ies have shown that the risk of di­a­betes is at least 25 times higher than the 0.1%-0.2% averred in the Lancet, he says.

Data on statin ben­e­fits de­rives from an anal­y­sis based on in­di­vid­ual pa­tient data by the choles­terol treat­ment tri­al­lists’ col­lab­o­ra­tion, which Collins leads.

De­spite nu­mer­ous re­quests, this has not been pub­lished — or in­cluded in the Lancet pa­per, says Sul­tan. This means the ev­i­dence on statin harm is “not as rig­or­ous as the ev­i­dence for statin ben­e­fits”.

“Ideally, all clin­i­cal trial data should be avail­able for third-party scru­tiny and pub­lished for pub­lic scru­tiny,” Sul­tan says.

The need for in­de­pen­dent re­view is “es­pe­cially press­ing in this case, given the pub­lic health im­pli­ca­tions of the call for wide­spread use of statins for pri­mary pre­ven­tion”.

Sul­tan’s pre­scrip­tion for a healthy heart is pri­mary pre­ven­tion: a Mediter­ranean-style diet, reg­u­lar phys­i­cal ac­tiv­ity, no smok­ing, no al­co­hol, lots of “good wa­ter” daily, no re­fined su­gar, no heavy meal af­ter 7pm, and lots of “good love”.

Top Bri­tish car­di­ol­o­gist Aseem Mal­ho­tra is sim­i­larly dis­mis­sive of the Lancet re­view.

“There is great con­cern among doc­tors about the re­li­a­bil­ity of in­dus­try-spon­sored tri­als,” says Mal­ho­tra. “Such stud­ies should be seen as mar­ket­ing un­til proven to be oth­er­wise.”

The Lancet re­view ap­pears aimed at shut­ting down the de­bate on statins de­spite con­sid­er­able con­tro­versy that still swirls around the drugs.

In ef­fect, it is “an­ti­science”, Mal­ho­tra says. There is “an epi­demic of mis­in­formed doc­tors and mis­in­formed pa­tients” glob­ally, he says.

 ?? Pic­ture: IS­TOCK ?? While a study claims the ben­e­fits of statins out­weigh the risks of tak­ing them, op­po­nents of the drugs re­main con­cerned about its se­ri­ous side ef­fects that in­clude mus­cle, nerve, liver and car­dio­vas­cu­lar dam­age, en­docrine dis­rup­tion, erec­tile...
Pic­ture: IS­TOCK While a study claims the ben­e­fits of statins out­weigh the risks of tak­ing them, op­po­nents of the drugs re­main con­cerned about its se­ri­ous side ef­fects that in­clude mus­cle, nerve, liver and car­dio­vas­cu­lar dam­age, en­docrine dis­rup­tion, erec­tile...
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