Treatment of H pyloriAssociated Ulcers

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The primary goal of H. pylori therapy is to completely eradicate the organism using an effective antibiotic-containing regimen. Reliance on conventional acid-suppress-ive drug therapy alone as an alternative to H. pylori eradication is inappropriate because it is associated with a higher incidence of ulcer recurrence and ulcer-related complications. Reinfection rates are generally low after the initial course of therapy as long as the patient has received a regimen with proven efficacy and is compliant with it. The H. pylori regimen that is chosen should have a per-protocol cure rate of 90% or more or a cure rate based on intention-to-treat analysis of 80% or more.9 In addition to proven efficacy, the optimal treatment regimen should cause minimal adverse events, have low risk for the development of bacterial resistance, and be cost effective.9

H. pylori treatment regimens are presented in Table 18-3. Eradication therapy with a PPI-based three-drug regimen should be considered for all patients who test positive for H. pylori and have an active ulcer or a documented history of either an ulcer or ulcer-related complication. Different antibiotics should be used if a second course of H. pylori eradication therapy is required.

The first-line regimen should contain a PPI plus clarithromycin and either amoxicillin or metronidazole. Amoxicillin should not be used in penicillin-allergic patients, and metronidazole should be avoided if alcohol is going to be consumed. The combination of two antimicrobials and a PPI leads to cure rates greater than 80% (by

intention-to-treat basis) and reduces the risk of selecting out resistant organisms. A single daily dose of a PPI may be less effective than twice daily dosing when used as part of a triple-drug regimen. Substitution of one PPI for another is acceptable and does not appear to affect eradication rates. Monotherapy with a single antibiotic or antiulcer agent is not recommended due to high failure rates. In the United States, two-drug regimens consisting of a PPI and an antibiotic are also not recommended.

The duration of therapy is controversial and varies by continent. Europeans routinely treat patients for 7 days whereas Americans usually rely on a 14-day regimen. While these seven additional days of therapy improves the absolute cure rate by approximately 9%,14 longer courses decrease compliance and increase drug cost.

Bismuth-based four-drug regimens have clinical cure rates similar to three-drug, PPI-based regimens. Bismuth-based regimens usually include tetracycline, met-ronidazole, and an antisecretory agent (e.g., PPI or histamine2-receptor antagonist [H2RA]). Bismuth salts promote ulcer healing through antibacterial and mucosal protective effects. While cheaper than most other regimens, drawbacks of bismuth-based regimens include the frequency of administration (four times a day), risk for salicylate toxicity in patients with renal impairment, and propensity for bothersome side effects (e.g., stool and tongue discoloration, constipation, nausea, and vomiting).

Nsaids Ulcers
FIGURE 18-3. Approach to the patient presenting with ulcer-like symptoms. (GERD, gastroesophageal reflux disease; HP Helicobacter pylori; H2RA, histamine2-receptor antagonist; NSAID, nonsteroidal anti-inflammatory drug; NUD, nonulcer dyspepsia; PPI, proton pump inhibitor.) (From Ref. 37.)

The combination product Pylera (bikalcitrate potassium 140 mg, metronidazole 125 mg, and tetracycline 125 mg) when used in combination with omeprazole 20 mg twice daily (before breakfast and dinner) is as effective as omeprazole-amoxicillin-clarith-romycin (OAC) in eradicating H. pylori in patients with DU. Although not FDA-ap proved for patients with GU, it would be expected to be effective in eradicating H. pylori in patients with GUs. The usual dose of Pylera is three capsules four times daily after meals and at bedtime with 8 oz. water for 10 days. The simultaneous administration of tetracycline and a metal-containing product (e.g., many antacids) may result in complexation and reduced tetracycline absorption. Consequently, the bismuth salt and tetracycline are physically separated in the capsule formulation of Pylera.

Helidac is a package of 14 blister cards with each card containing a single-day supply of bismuth subsalicylate (two 262.4-mg chewable tablets four times daily), metronidazole (250 mg tablet four times daily), and tetracycline (500 mg capsule four times daily). Unlike Pylera, Helidac is not a combination product; all three medications must be taken four times daily for 14 days in combination with an H2RA rather than a PPI.

The acquisition cost for a 10-day course of Pylera and a 14-day course of Helidac is more than $200, which is substantially more expensive than the cost of prescriptions for generic metronidazole and tetracycline and a bottle of nonprescription bismuth subsalicylate.

Patients may remain infected with H. pylori after the initial course of therapy because of reinfection, nonadherence with the initial regimen, or antimicrobial resistance. Factors associated with decreased adherence include use of a large number of medications, a need for frequent drug administration or long treatment duration, and the use of drugs that may cause intolerable side effects. Potential adverse drug events include taste disturbances (clarithromycin and metronidazole), nausea, vomiting, abdominal pain, and diarrhea. Superinfections with oral thrush or vaginal candidiasis can occur.

Table 18-3 Drug Regimens to Eradicate Helicobacter pylori"

Treatment Pfrgipifn

Two Drygi.

Vncwk-lui I y llirrc rimrt ¿dJy 4 OmLvaSok- 20 ihg [wu liOVSa Jay Clafiihrumytiri SCO nig qhnee tiiines adiy + orr>ififa7nle ¿1) ring daily Clifilhumnytin 500 my iIiilt (iiTK-vodoiy h RK 400 mg lwu ripus jdjy Three Drugs

0.yi;hrurny(in 50O rriy (¡rTn"i di(y 4 rrtL'lrr.*iiiAii^lc 5CQrrl(j [iro |iirn."v tuAiy t Om^iaA ¿0 tmlMKi Hk'f

Clafilhroniirtin 500 mg lwo time; a day 4 amrwic illin I g ivaj tirne^ a day 4 lapsopr arah? 30 mq lwo dm« a day Cljiahiomytln S0O nig 1vuo times a day 4 rneirondaKjIi? SCO mg two ilnnjs a djy + RBC 400 mg two times a day

^jMfKHkillif-, I : | [inw i day + iL'irirkifLiirryiir'i 5QO n hj tWO Hffl« a I Lay 4 Wit 400 rt kj ttifl till'"". ,b dty

Four Drugt

RSi nig icxM rinriii a day * miHronidWBli1 250 mg four [inw adAy 4 [wrAfyfiin^ SOD mg four iini«a ctiy + N ItA

(oonweivnonal Jeer-healing dosef Bi in:■ inr-tos i di/ ^ nrn'tionidwtJe 250 my ftjiJi (im« idjy + ^mo«ii illm 50Off*| fewluia^ j ti*y mm

(oonuwil'oral Jeer-healing (JosesJ IS5 525 IlKjfiX* iifill« i t JHWonKliiKile * KlttOddllin * PPI"

Pyleia SjisnnjlhiiutKituti jjctiiiurn MO mg + rnelnni^Jazole mg 4 letiatydkie 125 mgO (wo times a day and i ii i ii -jim/CIII 1 X") m:j iwu I :nK"h .14ity

PtX* hoof Fur

&>sd i^cciicTit Good-esoccllenr Good Good cViod-eafeiiHiT

OtoJ

Good-e/iellent

Good-enielleni

Good

Good-excellent rckuc therapy

BSi 525 mg ftyjjliirei a day metronidazole 500 ring (our tmws a day 4- teliaiycline 500 mg four nmesa day +

omeprazole 20 mg twrj ftneia day l-urazolkkmeiOO mq times a day 4 amo*k"'ilfl I g times a day 4 omeprazole 20 mg two (unesa day Arnmiii nig two times a U.iy 4 rifabutin JUO ring rtaily > pantopraxjeaO mtj twrirriesa nay bsi bismuth suLh.i cytais h.lta, Hiieteproi amagonni; ppt ff&nn pumpVihblGT rbt, raiirirfine tHimuih citraw (tkm auiiahle in the UniKd Slate;).

■TlfM.'ir.'g iirmi tuned cm ciiitiM.y iuf a H-ctjy UWlmWt duralkmunkv! athnnviscnplL'd.

lHW(l on InH^iisri-TKi-Tnfsq in^is fwtKTn fiefiireiK« 3,12. 1J, and 35,*lv?ie: poof IttiTlyrt erifftirion. fair - 7CH. [dWt. (food - SO* to«*, ind exceHefil -greal« than SMt.

therapy should In: continued lor anadditionaJ 2 wseks. Onafian cJ thfrapiy ii 7 no 10 donn, 'Givin ioi ^diyi, J(TJ\ifn fnr 10 day*.

Pre-existing antimicrobial resistance is an increasing cause of treatment failure and is estimated to account for up to 70% of all treatment failures. Geography is the most important factor in H. pylori resistance. Metronidazole -resistant strains are more prevalent in Asia (85%) than North America (30%).15 Primary resistance to amoxicillin and tetracycline remains low in both the United States and Europe. Clarithromycin resistance rates are estimated to be approximately 10% in the United States. Another confounding factor when evaluating potential antibiotic resistance is that culture and sensitivity studies are not routinely performed with H. pylori infection.

Initiation of a second H. pylori treatment regimen after failure of the initial treatment regimen is usually associated with a lower success rate. Reasons for failure are often the same as those reported with failure of the initial regimen: patient noncompliance and/or antimicrobial resistance. In these situations, quadruple therapy for 14 days is generally required, and metronidazole or clarithromycin should be replaced by another antibiotic if either one of these agents was used in the initial regimen. If both clarithromycin and metronidazole were used as initial therapy, a regimen consisting of furazolidone 100 mg four times a day with tetracycline, bismuth, and a PPI can be used. Another second-line regimen consisting of a PPI, amoxicillin 1 g twice daily, and rifabutin 300 mg once daily for 10 days resulted in eradication rates greater than 80%.16,17

Treatment of NSAID-lnduced Ulcers

Treatment and dosing recommendations to heal NSAID-induced GU or provide maintenance therapy in patients receiving NSAIDS are shown in Table 18-4. Choice of regimen in a patient with PUD related to NSAID use depends on whether NSAID use is to be continued. NSAIDs should be discontinued if possible and replaced with alternatives (such as acetaminophen) although this may not be desirable or feasible in some patients. For patients discontinuing NSAID therapy, PPIs, H2RAs, or sucralfate are all effective for ulcer healing. PPIs are usually preferred because they provide more rapid relief of symptoms and ulcer healing than H2RAs or sucralfate.1 , 7 For patients continuing NSAID therapy, PPIs are preferred over H2RAs or sucralfate because potent

18_21

acid suppression is required to accelerate ulcer healing. Ifthe decision is made to continue NSAID therapy, adjunctive strategies may be required to promote ulcer healing and prevent future recurrences.

Table 18-4 Oral Drug Regimens to Heal Peptic Ulcers or Maintain Ulcer Healing in the Absence of Antibiotic Therapy

Drug

Mai ntenance of ÜU orGU Healing (mg/day)J_

Mucosal Protectant

Sucralfate 1 g four times a day

2 g two times a day

H -Receptor Antagonists

Cimetidine

Famotidine Nizatidine

Ranitidine

300 mg lour limes a day 4-00 mg two times a day 300 nhg at bedtime 20 mg two times a day 40 mg at bedtime 150 mg two times a day 300 mg at bedtime 150 mg two times a day 300 mg at bedtime

Proton Pump Inhibitors

E som eprazo le 20-A 0 mg daily

Lansoprazole Omeprazole Panloprazole Rabeprazole

15-30 mg daily 70-40 mg daily 40 mg daily 20 mg daily

1 g four times a day 1-2 g two times a day

400-800 mg daily

20-40 mg daily 150-300 mg daily 150-300 mg daily

20-40 mg daily 15-30 mg daily 20-40 mg daily 40 mg daily 20 mg daily

DLL duodenal uker; GlJj gastric ulcer.

■The lower do:e ir eacl J- - -ii ■: ■. m. n-5' o:r mended for DU; TI ■ ^ higher dose is recommended for GU,

Prevention of NSAID-lnduced Ulcers

Prophylactic regimens against PUD are often required in patients who require long-term NSAID or aspirin therapy for osteoarthritis, rheumatoid arthritis, or cardiopro-

tection. Misoprostol, H2RAS, PPIs, and COX-2 selective inhibitors have been evaluated in controlled trials to reduce the risk of NSAID-induced PUD. In patients at risk for NSAID-induced ulcers, PPIs at standard doses reduce the risk of both gastric andDU as effectively as misoprostol and are generally better tolerated.

Although acute GI bleeding is the most serious adverse outcome of NSAID therapy and is ultimately what clinicians are trying to prevent with prophylactic therapy, few studies have compared PUD prophylaxis strategies using this outcome measure. Acute GI bleeding is not usually evaluated in studies because of the low frequency with which bleeding occurs in NSAID users, the small size of most prophylaxis studies, and their short duration. Instead, studies usually rely on secondary outcome variables to evaluate efficacy such as the incidence of ulcers during screening endoscopy or the incidence of patient-reported ulcer symptoms. Correlation between these secondary outcomes and PUD-related bleeding events is poor and thus, clinicians must be cautious when extrapolating the results of these studies to patient care.

Misoprostol

Misoprostol is a synthetic PG E1 analog that exogenously replaces PG stores. It is indicated for reducing the risk of NSAID-induced GU in patients at high risk of complications from GU (e.g., the elderly and patients with concomitant debilitating disease), as well as patients at high risk of developing gastric ulceration, such as patients with a history of ulcer. The minimum effective dose shown to inhibit acid se-

22 23

cretion and promote mucosal defense is 400 mcg/day. ' Misoprostol use is limited by a high frequency of bothersome GI effects such as abdominal pain, flatulence, and diarrhea.24-2 Misoprostol is contraindicated in pregnancy due to potential abortifa-cient effects. Arthrotec is a combination product that contains diclofenac (either 50 or 75 mg) and misoprostol 200 mcg in a single tablet.

H2-Receptor Antagonists

Refer to Chapter 17, for more information on the H2RAs. Standard doses of H2RAs (e.g., famotidine 40 mg/day) are effective in preventing NSAID-related duodenal ulceration but not gastric ulceration (the most frequent type of ulcer-associated with NSAIDs). Higher doses (e.g., famotidine 40 mg twice daily) may reduce the risk of gastric and duodenal ulceration in NSAID users, but results from clinical trials are variable.

Proton Pump Inhibitors

Refer to Chapter 17 for more information on the PPIs. PPI therapy is more effective than H2RAs in reducing the risk of nonselective NSAID-related gastric and duodenal ulceration. PPIs are also as effective as misoprostol but better tolerated. All PPIs are effective when used in standard doses. In patients who experience a PUD-related bleeding event while taking aspirin but who require continued aspirin therapy, the ad-

dition of a PPI reduces the incidence of recurrent GI bleeding. Prevacid NapraPAC provides naproxen (either 250, 375, or 500 mg) and lansoprazole 15 mg in individual blister packages.

COX-2 Selective Inhibitors

With the availability of NSAIDs with COX-2 selectivity, clinicians postulated that these agents would avoid the need to add an additional prophylactic agent in patients with PUD risk factors. However, selective COX-2 inhibitors are no more effective than the combination of a PPI and a nonselective NSAID in reducing the incidence of ulcers and are associated with a greater incidence of CV events (e.g., ischemic stroke). Celecoxib is the only agent in this class that remains on the market; its postulated improved GI safety when compared to nonselective NSAIDs has not been established. 8,29 In addition, controlled studies demonstrated that celecoxib is no better

than the combination of diclofenac and omeprazole.

Longer-term studies evaluating the CV risks associated with the use of COX-2 inhibitors have found a higher incidence of CV mortality with these agents compared

31 32

to traditional NSAIDs. ' This prompted the withdrawal of both rofecoxib and val-

decoxib from the market and the inclusion of a black box warning in the celecoxib

package insert. Given the CV risk of the COX-2 inhibitors, a nonselective NSAID and a PPI is recommended instead of celecoxib in patients at high risk for NSAID-related PUD.5-34

Sucralfate

Sucralfate is a negatively charged, nonabsorbable agent that forms a complex by binding with positively-charged proteins in exudates, forming a viscous, paste-like, adhesive substance. This forms a coating that protects the ulcerated area of the gastric mucosa against gastric acid, pepsin, and bile salts. Limitations of sucralfate include the need for multiple daily dosing, large tablet size, and interaction with a number of other medications (e.g., digoxin and fluoroquinolones).

Adverse effects of sucralfate include constipation, nausea, metallic taste, and the possibility for aluminum toxicity in patients with renal failure. While sucralfate may be used for the treatment of an NSAID-related ulcer when NSAID therapy is being stopped, it is not recommended for use as prophylaxis against NSAID-induced ulcers.

Conventional Treatment of Active DU and GU and Long-Term Maintenance of Ulcer Healing

Conventional therapy prior to the advent ofH. pylori eradication therapy consisted of standard doses of sucralfate or an H2RA for 6 to 8 weeks. A PPI provides equivalent efficacy with treatment duration of only 4 weeks. Long-term antiulcer therapy is ineffective for treating H. pylori infections.

® Low-dose maintenance therapy with a PPI or HjrRA is only indicated for patients who fail H. pylori eradication, have H. pylori-negative ulcers, or develop severe complications related to ulcer disease. Drug regimens and doses are presented in Table 18-4.

Treatment of Refractory Ulcers

The presence of refractory ulcers (ulcers that persist beyond 8 weeks [DU] or 12 weeks [GU]) requires thorough assessment, including evaluation of medication compliance. The patient should be questioned regarding recent NSAID ingestion. Tolerance has been reported with as few as 4 weeks of H2RA therapy, and thus a change to PPI therapy should be considered in this situation.35 Other assessments that maybe considered include an ulcer biopsy to exclude malignancy, H. pylori testing (if not done initially), a serum gastrin measurement to exclude ZES, and gastric acid studies. In one study, increasing the starting dose of PPI therapy healed 90% of refractory ulcers after 8 weeks of therapy.36

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