CARES on Febuxostat 3/3 Application and My Views

I started reading of the red flags over the cardiovascular safety of febuxostat while preparing for a talk to be given during UP Medicine’s Grand Scientific Symposium (2014?). I included data from the meta of Tayar JH (2012) to spark interest in monitoring developments. I belatedly came across the article of WB White in the American Heart Journal (2012) describing the study design for CARES. It’s quite fortunate that 4 years later I’m finally reading of the results. Interestingly, a trial using a PROBE design (allegedly it approximates real world experience better than RCTs) in determining CV safety of febuxostat (vs. allopurinol) had been described in BMJ Open (2014) by MacDonald TM, et al. – The Febuxostat versus Allopurinol Streamlined Trial (FAST).

Let me differentiate the application of CARES study in different patient scenarios.

In patients with known CV disease (prior MI, stroke/ TIA, peripheral vascular disease, unstable angina and diabetes with vascular complications), I’d choose allopurinol as my primary urate lowering drug. Since pegloticase is not available in the Philippines, I’d offer febuxostat as an alternative when the patient develops severe AEs or cannot tolerate allopurinol.  And it’s use should be with full disclosure of the increased risks for CV deaths. As of now, it is not yet known whether aggressive risk modification (ASA, NSAID avoidance, statins, etc) would off-set the increase in sudden cardiac deaths. Right now, I’m already thinking of reviewing my febuxostat treated patients and will probably shift to allopurinol if without contraindications.

In patients without CV disease, the use of febuxostat in treating hyperuricemia may remain unchanged. There are still no studies to suggest a change in practice. But a little caution should be exercised probably in handling patients with higher CV risk (and yes, we’d probably need to start using CV risk calculators in the clinic for this). I wouldn’t hesitate using febuxostat in gout patients with low CV risks (some NSAID trials define this as an estimated 10 year risks of CV mortality <10%). However, for those with high CV risk (estimated 10 year risk of CV mortality >10%), I’d probably be more careful in using febuxostat but the drug still remains an option. Of course, it follows that aggressive risk modification should be implemented. I’d still use febuxostat unless the FDA issues a black box warning for the drug.

Some of you may be wondering why I still prefer placing patients on febuxostat rather than completely shifting all my patients to allopurinol. One word. COMPLIANCE. Regardless of dose, Febuxostat is given as a once a day pill. And if you have a patient being treated for multiple conditions (think HPN, HF, dyslipidemia), then having a once-a-day pill can mean a big difference in compliance.

Notice that I didn’t mention efficacy. If you back read my posts, it was only the febuxostat 80mg which was better than allopurinol 300mg in bringing down urate levels to target. In fact, as a personal rule of thumb, allopurinol 300mg may be as effective as febuxostat 40mg in bringing down SUA <6mg/dl. (Therefore, allopurinol 600 mg/d may be as effective as febuxostat 80mg/d). Maximizing allopurinol use (yes, it can be used to 800mg/d!) can bring about similar outcomes in reducing urate levels. Likewise, combining allopurinol with other drugs with uricosuric properties (losartan, fenofibrate) may help achieve those targets. If you bothered to check the secondary endpoint of the CARES study, the proportion of patients who experienced a treatment needing flare and those who achieved SUA <6mg/dl were almost comparable between groups. Allopurinol remains an effective urate lowering drug, we just have to learn to maximize it. And, please, no more Hande protocol!

The CARES study just complicated an already challenging disease to treat. It’s challenging because gout is a very treatable disease and successful management of hyperuricemia can avert complications and repeated attacks. Now aside from NSAIDs, we’d have to be wary of the impact our ULT has on heart health. Hopefully, we are clarified of this issue once the results of FAST come out (and hopefully, a meta-analysis can come out).


CARES on Febuxostat 2/3 The Appraisal

For my mentor (HMR) who’s fond of how investigators name their trials, the full name of the study was “CArdiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular ComoRbiditiES“. The article discussing the results was published in the NEJM just last 12 March 2018. A link to the article can be found here.

PATIENTS. The CARES study was a multi-center (from the US, Canada and Mexico), randomized, active-control, non inferiority trial among patients with gout and cardiovascular disease.

Cardiovascular disease was defined as any of the following:

  • Myocardial infarction (but not in the 2 months preceding the randomization)
  • Hospitalized unstable angina
  • Stroke (but not in the 2 months preceding the randomization)
  • Hospitalized transient ischemic attack
  • Coronary or cerebral revascularization procedure
  • Peripheral vascular disease
  • Diabetes mellitus with evidence of micro- or macro-vascular disease (retinopathy, nephropathy, neuropathy or small vessel disease)

Gout was diagnosed using the older ARA Criteria (Wallace) and not the newer 2015 ACR EULAR Criteria.

INTERVENTION/ COMPARISONS. Patients were to receive either febuxostat or allopurinol. Randomization was done based on renal function.

Patients randomized to febuxostat received 40mg initially regardless of renal function. The dose was increased to 80 mg after 2 weeks if SUA was not <6mg/dl. Patients with GFR >60ml/min and randomized to allopurinol received 300mg initially and the dose was titrated by 100mg until a max dose 600mg/d or the target SUA was achieved. Those with GFR 30-60 ml/min, received allopurinol 200mg initially then titrated up by 100mg until a max dose 400mg/d or the target urate levels were reached.

All patients received colchicine 0.6 mg/d for the first six months. If colchicine couldn’t be tolerated, either naproxen 250 mg BID + lansoprazole 15 mg OD (if eGFR>50ml/min) or prednisone <10mg/d (if eGFR<50ml/min) were given. There was no specific duration of treatment as termination of the trial hinged on the accrual of 624 Major Adverse Coronary Events.

OUTCOME. The primary endpoint was the occurrence of Major Adverse Coronary Events (MACE) which includes: CV death, non-fatal MI, non-fatal stroke and unstable angina with urgent coronary revascularization.

Secondary endpoints were the: (1) mean number of flares from the end of the first to the end of the fifth year; (2) percentage of patients with tophi resolution by the end of the fifth year; (3) Anti-Platelet Trialist Collaboration (APTC) endpoint – which is basically MACE excluding unstable angina; (4) Pre-defined CV endpoints such as hospitalized CHF, arrhythmias, venous or arterial peripheral thromboembolic events and TIAs; (5) Proportion of patients achieving SUA <6mg/dl at end of years 1-5.

Were patients randomized to treatments? Yes. via IVRS.

Were the groups similar at the start of the trial? Yes. See Table 1 of the article.

Were groups treated equally? Yes. The protocol (available as a supplement) provided details on this.

Were all patients accounted for? Yes. And there was a big number of patients who discontinued trial treatment (57.3% vs. 55.9%) and who did not complete the trial visits (45% vs 44.9%) in both the febuxostat and allopurinol arms, respectively. (If you had doubts about the PRECISION trial over the high dropout rates, then …)

Were patients analyzed in the groups they were randomized? Yes. The modified ITT just did not include the patients who never received treatment. A total of 6190 patients were included in the analysis. Only 8 patients were excluded from the mITT.

Were patients and clinicians blinded to treatment? Yes. And it appears the outcome assessors were too.

What were the results? The outcome of interest was the MACE. You may read the article if you’re interested in other outcomes.


There were significantly more CV deaths and Death from any cause in the febuxostat-treated patients. That’s 34% more CV related deaths and 22% more deaths from any cause in the febuxostat group. Hence, the grave concern over the results of this study.

Now, here’s heading to the study supplement and looking at the breakdown of causes of CV deaths.

Adjudicated Causes of CV Deaths (CARES Study

We see that most of the CV related deaths were from sudden cardiac death (defined as death that occurs unexpectedly in a previously stable patient and includes the following deaths: (1) witnessed and instantaneous without new or worsening symptoms; (2) witnessed within 60 minutes of the onset of new or worsening cardiac symptoms; (3) witnessed and attributed to an identified arrhythmia; (4) subjects unsuccessfully resuscitated from cardiac arrest or successfully resuscitated from cardiac arrest but who die within 24 hours without identification of a non-cardiac etiology; and, (5) unwitnessed death or other causes of death.) And a review of all-cause mortality revealed that the increase was brought about by these CV deaths – specifically SCDs.

An interesting association with the study was the impact of some patient characteristics on CV deaths. The relative risks for the following factors wereas follows:

  • NSAIDs use: RR 2.17 (95% confidence interval 1.28, 3.68)
  • Colchicine as prophylaxis: RR 1.38 (95% confidence interval 1.05, 1.81)
  • Non-colchicine as prophylaxis: RR 1.09 (95% confidence interval 0.53, 2.23)
  • Non-use of low dose ASA: RR 1.99 (95% confidence interval 1.39, 2.85)
  • Use of low dose ASA: RR 0.85 (95% confidence interval 0.58, 1.24)
  • Non-use of insulin among DM: RR 1.46 (95% confidence interval 1.06, 2.00)
  • Use of insulin among DM: RR 1.13 (95% confidence interval 0.86, 1.66)

These would suggest that agents other than colchicine be used for gout prophylaxis (in the study, most patients intolerant to colchicine were given naproxen followed by steroids). We do not know if limiting the duration of colchicine use would reduce the flares.

Now some may be wondering why using NSAIDs for prophylaxis didn’t result in increased CV deaths but NSAID use was. Well, I suspect 2 reasons: 1. There is a difference in the dose used for prophylaxis vs treatment of flares. We use higher doses when treating flares and there is a dose-dependent relationship between NSAIDs and CV events. Even in the CNT meta-analysis, we see that rates of CV events increased with NSAID dose (at least, for most agents). And, (2) the NSAID used for prophylaxis was naproxen which has comparable COX1: COX2 activity as ASA (only reversible). Naproxen has long been “believed” to be the most heart-friendly among the NSAIDs. Unfortunately, it’s notorious for causing GI upset.

And if patients need glycemic control, insulin is the preferred agent.

CONCLUSIONS. While rates of major adverse cardiovascular events were similar between groups, all cause mortality was significantly higher (22% more) among febuxostat treated patients – which were driven mostly by an imbalance in CV-related deaths, particularly SCDs. Rates for other components of the MACE (non fatal MI/ stroke, UA needing revascularization) and other predefined CV safety outcomes (arrhythmia, peripheral vascular disease and HF) were not statistically different. The impact of using some drugs to minimize risks of CV related deaths warrants a separate study.

THESE ARE TROUBLING RESULTS. Do we now stop using febuxostat because over these concerns? Will febuxostat go the way of rofecoxib?

Next: Applying the Results to Patient Care and My Take of the Results

Reference article: White WB, Saag KG, Becker MA, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. NEJM 2018; 378: 1200-1210.

CARES on Febuxostat 1/3 The Scenario

It was welcome news when febuxostat was introduced to the Philippine market. Pinoys have long been identified in rheumatology texts as one of the groups with the highest prevalence of gout. A local study found that, among the 25% of the population with hyperuricemia, 1.6% actually had gouty arthritis (1). That’s 1.6 million people needing treatment for the condition. Sadly, 50% of these patients have complications (i.e. tophi or kidney stones) by the time they seek medical consult (2). And the lure of using febuxostat was made more attractive when the local distributor introduced it at a very competitive price – PhP26 or ~US$0.50 – compared to the Western markets (I heard it was US$10).

Prior to febuxostat, allopurinol was the go to drug for treating hyperuricemia. Aside from uricosurics being more expensive and often unavailable (as of now, both probenecid and sulfinpyrazone are no longer available in the Philippines), many patients preferred the convenient once a day dosing of allopurinol. Unfortunately, many physicians limit their use to either 100 or 300mg. On checking local drugs references (MIMS, PPD), 300 mg was cited as the maximum allowed dose. This is in contrast to the 800mg allowed in the US or 900mg in the EU. You would infrequently encounter a patient with >300mg allopurinol. And, if ever you do, the dose would be reduced (instead of maintained) as soon as urate levels normalize.

Strong concerns over SJS, TENS and allopurinol hypersensitivity syndrome made going beyond 300mg very unattractive. And as if that were not enough, concerns over the impact of renal impairment (on allopurinol-related adverse events) lead many to abide by the Hande protocol when starting the drug. So really, Pinoys on allopurinol were not really maximizing the use of the drug.

The first two years of industry-sponsored talks focused on 80mg febuxostat being more effective than 300mg allopurinol in bringing down serum urate levels to <6mg/dl. The safety profile of febuxostat 40mg was comparable to allopurinol 300mg. And only GI adverse events (transaminitis, abdominal discomfort) increased with higher doses of febuxostat. The incidence of skin reactions were similar between the two drugs (although, personally, I have yet to encounter a patient who developed them on febuxostat). Since the two drugs were structurally different, febuxostat was initially indicated as an alternative to allopurinol when a patient developed a hypersensitivity reaction. However, when the target for tophaceous gout was pegged at <5mg/dl, many looked past this indication and preferred starting patients on febuxostat. And soon enough, even practice guidelines (3) suggested choosing between the alllopurinol and febuxostat as first line drugs for hyperuricemia in gout. No longer was febuxostat an alternative, it became an option. And, for the first time in the Philippines, costs wasn’t much of a factor (compared to our Western counterparts) in choosing one drug over the other.

Towards the third year, we started hearing about possible alarms over the CV safety of febuxostat. Doing a meta-analysis of febuxostat RCTs (4) showed no significant difference in cardiovascular events. In fact, the meta-analysis showed a lower risk of CV events with febuxostat (40/ 80mg) compared to allopurinol (200/ 300mg). However, the 95% confidence intervals suggested NO statistical difference. But we have to realize that none of the first RCTs were actually designed to detect significant differences in these adverse events. And doing a network meta was just a way to find evidence on a concern not yet properly addressed by any existing RCT. (Note to self: Ask Drs Tony and Inday Dans which is better between the two – a network meta of secondary endpoints or an RCT having it as a primary endpoint.)

Here is where the Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout Study or CARES Study comes in. It’s the first RCT to directly address this concern over the CV safety of febuxostat. And in contrast to FACT, APEX, FOCUS, EXCEL and CONFIRMS, this had CV safety as the primary endpoint while efficacy was checked as a secondary endpoint. You can find a link to the article here.

Next: The Appraisal of CARES Study


  1. Salido EO, et al. Phil J Int Med 2008; 46: 273-6.
  2. Roberto LC, et al. Poster Presentation. PRA Annual Meeting 2017.
  3. Khanna D, et al. 2012 American College of Rheumatology Guidelines for Management of Gout. Part 1. Arth Care & Res 2012; 64 (10): 1431-46.
  4. Tayar JH, et al. Febuxostat for treating chronic gout. Cochrane Database of Sys Rev 2012; 11: Art No CD008653.

Masakit ang likod ko, Doc!

Kailan dapat kumonsulta na sa manggagamot

Hot_LBP_thumb.jpgWalo sa bawa’t sampung tao ay makakaranas ng pananakit ng kanilang likod. Sa 30%, ang karamdamang ito at pabalik-balik. At sa 30% naman ay maaaring makaranas ng matagalang panananakit ng likod (o chronic low back pain). Maaari itong maging sanhi ng pag-aalala. Seryoso na ba ang nararamdaman ko? Malulumpo na ba ako?

Ang mabuting balita ay sa 90% ng mga dumadanas ng pananakit ng likod, ito ay hindi seryosong sakit at inaasahang gagaling.

Maaaring napagod lamang ang mga muscle sa likod sa matagal o mahirap na gawain o di kaya’y nanibago lang sa bagong ginagawa o trabaho. Kailangan lang tulungan ang likod na gumaling sa pamamagitan ng pagpapahinga, pag-iwas sa pagbuhat ng mabibigat na bagay at pag-inom ng gamot para sa kirot. Hindi rin magandang matagal mamahinga sa kama. Salungat dito, ang pagpapahinga sa kama (o bed rest) ng mahigit sa 2 araw ay maaaring mas makasama at maging sanhi ng hindi agad pagbalik sa dati ng likod. Sa halip, matapos ng ilang oras ng pagpapahinga, inaabisuhan namin na dahan-dahang bumalik sa dating gawain.

Limang porsyento (5%) ng mga dumadanas ng pananakit ng likod ay may seryosong karamdaman na kailangan maagapan upang maiwasan ang disabilidad o pagkalumpo.

Ano ang mga palatandaan na maaaring seryoso na ang iyong nararamdaman? Kung ikaw ay meron ng mga sumusunod kasabay ng pananakit ng likod, mas mainam na magpatingin agad sa isang manggagamot:

  • Pananakit ng likod matapos maaksidente
  • Pananakit ng likod na mas malala kapag nagpapahinga
  • Pananakit ng likod na gumigising sa iyo tuwing gabi
  • Nakaraan o kasalukuyang paggamit ng steroids
  • Nakaraan o kasalukuyang kanser
  • Di maipaliwanag na pangangayayat
  • Paggamit ng mga gamot na nakapagpapahina ng immune system
  • Paggamit ng illegal na gamot (tulad ng shabu at marijuana)
  • Lagnat
  • Hindi na makontrol o mapigilan ang pagdumi o pag-ihi
  • Panghihina ng mga hita o binti
  • Bawas o kawalan ng pakiramdam sa bandang ari o puwet
  • Paninikip (o stiffness) ng likod pagkagising sa umaga na tumatagal ng mahigit 45 minuto

Ang mga kondisyon sa itaas ay tinatawag na “red flags” sa pananakit ng likod. Ibig sabihin nito ay maaaring may seryosong karamdaman (tulad ng impeksyon, pagkabali ng buto o fracture, kanser or spondyloarthritis) na sanhi ng pananakit ng likod. Kailangang magpasuri kaagad sa manggagamot para malapatan agad ng tamang gamot. Ito ang mga kondisyong hindi na dapat I-bale wala.

Ang natitirang 5% ay mayroong kondisyon sa likod na nangangailang ng pagsubaybay o gabay ng duktor.

Kabilang sa grupo na ito ang pagkakaroon ng osteoarthritis, spondylosis, pagkawala sa alignment ng mga buto (scoliosis o spondylolisthesis), atbp. Ang iba rito ay maaaring gumaling sa tamang gamutan. Ngunit kadalasan sa mga natitirang 5% na ito, ang pananakit ng likod ay magiging “chronic” o matagalang kondisyon na kailangan ng iba’t ibang pagpapagamot upang mabawasan ang hirap na dulot nito.

Maraming maaaring sanhi ang pananakit ng likod. Kung ito ay may kasabay na mga kondisyon tulad ng mga nakalista sa itaas o di kaya’y ito’y higit na sa 3 buwang nararamdaman, mas mabuting ikonsulta na ito sa duktor sa halip na ipagkatiwala ito sa iba pa.


Bakit ako naka gamot para sa malaria? Eh, lupus ang sakit ko!

Ang hydroxychloroquine (at ang kahalintulad na gamot nito, ang chloroquine) ay nabibilang sa grupo ng mga gamot na  ginagamit laban sa malaria (anti-malarial). Subalit matapos ang maraming taon, nadiskubre na ang hydroxychloroquine ay may epekto rin sa ilang uri ng arthritis at mga rayuma.

Ngayon ay itinuturing na disease modifying anti-rheumatic drug (DMARD) ang hydroxhloroquine dahil maaari nitong maiwasan na masira ang kasu kasuhan at mapababa ang posibilidad ng matagalang pagkabaldado (long term disability) sa ilang sakit na ito ay nakakitaan ng bisa.

Kabilang sa mga kondisyong nakakitaan ng bisa ang hydroxychloroquine ay ang mga sumusunod:

  • Systemic lupus erythematosus (SLE) na pinasimple sa pagtawag ng lupus
  • Rheumatoid arthritis
  • Juvenile idiopathic arthritis
  • Ilang auto-immune diseases

Hindi pa buo ang kaalaman sa kung papaano tumatalab ang hydroxychloroquine sa mga nasabing sakit subalit ang paniniwala ay inaabala nito ang komunikasyon sa pagitan ng mga immune cells ng isang pasyenteng may problema sa immune system. At sa pamamagitan ng pag-inom ng gamot nito, maaaring bawasan ang paggamit ng steroids (steroid sparing) at mabawasan ang pananakit at pamamaga ng mga kasukasuhan. At sa mga may lupus, ang paggamit ng hydroxychloroquine ay nakakabawas sa pagiging aktibo (flares) ng kanilang sakit. Kaya’t mula 2008, mas maraming rheumatologist ang nagrereseta ng gamot na ito sa kanilang pasyenteng may lupus.

Pag-inom ng gamot. Bago magsimulang uminom ng hydroxychloroquine ay kailangang malaman ng iyong duktor kung meron ka ng mga sumusunod na problema:

  • Allergy sa hydroxychloroquine, quinolone at sa quinine – na kung meron ay hindi puwede ituloy ang pag inom ng nasabing gamot
  • Problema sa mata – lalo na kung ang apektado ay ang retina o ang loob ng mata (macula)
  • Problema sa bato (chronic kidney disease o mataas ang creatinine sa dugo) at sa atay (cirrhosis o chronic liver disease)
  • Problema sa balat tulad ng psoriasis o sensitive ang balat sa sinag ng araw (photosensitivity)
  • Anemia o mababa ang pula ng dugo na maaaring dulot ng glucose-6-dehydrogenase (G6PD) deficiency

Kaya’t maraming duktor ang nagpapa-laboratoryo at nagpapa-clearance sa espesyalista sa mata (Ophthalmologist) bago magsimula ng gamutan.

Ang gamot ay mabibili sa dose na 200mg kada tableta. Ito ay maaaring inumin ng 1-2 tableta sa isang araw. Subalit ang abiso ng mga ophthalmologist ay huwag sumobra ang dose sa 5.5 mg kada kilogramo ng timbang ng pasyente. Kaya’t kung ang bigat mo ay 60 kg, hindi dapat lumampas ng 1 1/2 tableta sa isang araw ang iniinom na hydroxychloroquine para mabawasan ang posibilidad ng problema sa mata na dulot ng gamutan.

Side effects. Halos 10% ng mga pasyenteng umiinom ng hydroxychloroquine ay nakararanas ng pagduduwal, kawalan ng gana kumain o pagtatae. Ang mga problemang ito ay maaaaring mabawasan kung isasabay ang pag-inom ng gamot sa pagkain o pag-inom ng gatas. At minsan, kusang nawawala ang mga side effect kung itutuloy lang ang gamutan.

May iilan naman na nakararanas ng pamamantal ng balat o di kaya’y nagiging mas sensitibo sa araw. Sa ganitong dahilan ay maaaring mapalala ng hydroxychloroquine ang psoriasis. Kaya’t dapat gumamit ng sunblock/ sunscreen o di kaya’y sumangguni sa dermatologist para sa problema sa balat.

Ang iba naman ay nagkaka problema sa mata tulad ng panlalabo ng mata. Madalas ay nawawala ang problemang ito kung agad na maititigil ang gamot. Subalit, bibihira, ay nagdudulot ng mas seryosong problema sa mata ang hydroxychloroquine. Kaya’t importante na habang umiinom nito ay nagpapasuri ng mata taun-taon sa isang ophthalmologist. Mas madalas ang mga seryosong problema sa mata kung higit 5 taon ng gumagamit ng gamot o di kaya’y may problema sa bato at atay. Kaya’t kung sakaling meron man nito ang pasyente, kinakailangan ng mas madalas na pagbisita sa Ophtha – kaya 6 na buwan.

Ilang bihirang side effect na kaugnay ng paggamit ng hydroxychloroquine ay ang magnipis ng buhok, pamumuti ng balat at buhok, at panghihina ng mga muscle.

Ang hydroxychloroquine ay nakakatulong na mabawasan ang mga sintomas sa balat at kasu kasuhan, sa pagkontrol ng pamamaga ng katawan, sa pagbawas ng dose na ginagamit na steroids at maiwasan ang pagiging aktibo muli ng kanilang sakit sa mga pasyenteng mayroong lupus.