Histamine2-Receptor Antagonists

Standard Therapy for Acid-Peptic Diseases

Mark Feldman, M.D., and Michael E. Burton, Pharm.D.
N Engl J Med 1990; 323:1749-1755December 20, 1990DOI: 10.1056/NEJM199012203232507
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H2 Blockers in Peptic Ulcer Disease

Duodenal Ulcer
All four H2 blockers, when used in the doses shown in Table 1, are capable of healing
duodenal ulcer to approximately the same degree.203 204 205 206 207 208 209 210 The
average rates of healing with H2 blockers in several placebo-controlled studies among

outpatients are shown in Figure 3Figure 3

Rates of Healing of Duodenal
Ulcer and Gastric Ulcer during Treatment with H2 Blockers () or Placebo ().. The rates
of complete healing after two, four, and eight weeks of therapy averaged 51, 78, and 92
percent, all substantially higher than the rates of healing with placebo. It is apparent from
Figure 3 that the healing curve for duodenal ulcer may not have reached a plateau after
eight weeks of therapy with H2 blockers. Thus, although 8 percent of patients may still
have an unhealed ulcer after eight weeks, some of these ulcers will probably heal after an
additional four to six weeks of therapy. Moreover, about half the patients with unhealed
duodenal ulcers become asymptomatic with H2-blocker therapy.203 It is therefore quite
uncommon for a duodenal ulcer to remain unhealed and symptomatic after prolonged
therapy with H2 blockers. There is little evidence that higher initial doses of cimetidine
lead to higher rates of healing than those shown in Figure 3 but a higher-than-usual dose
of ranitidine may lead to slightly higher rates of healing at two weeks and faster relief of

symptoms.215 It is often convenient to administer the H2 blocker at bedtime, but similar

rates of healing can be achieved by giving the same dose in the morning.216
The objectives of therapy are the relief of symptoms and the prevention of complications.
The acceleration of healing is an objective of therapy only if it achieves one or both of
these goals. H2 blockers relieve the Symptoms of ulcer more rapidly than placebo, and
consequently these drugs reduce the use of antacids. There is not, however, a close
correlation between the relief of ulcer symptoms and healing,203 , 212 and it is difficult
to conclude with certainty that H2 blockers prevent complications such as bleeding,
perforation, or obstruction.217 However, the incidence of these complications was
significantly reduced, from 3.5 to 1.0 percent, with nizatidine.218 There is no evidence
that patients who present with a duodenal ulcer that is bleeding have a reduced rate of
rebleeding in the hospital if they are treated with H2 blockers.219 , 220
H2 blockers may also prevent complications when used as prophylactic agents after initial
healing. Although all four H2 blockers can prevent symptomatic and asymptomatic
recurrences of ulcer,221 222 223 224 until recently there was little evidence that
maintenance therapy prevents complications. As reported in an abstract by Jensen et
al.,225 patients with a bleeding duodenal ulcer that healed with ranitidine (150 mg twice
a day) were randomly assigned to maintenance therapy with either ranitidine (150 mg at
bedtime) or placebo for up to three years. Ranitidine was superior to placebo in
preventing rebleeding, although the rate of rebleeding in the patients taking ranitidine
was considerable (9 percent, vs. 36 percent in the placebo group).
Although maintenance therapy with H2 blockers, given at a reduced dose at bedtime, is
effective in preventing symptomatic relapses in patients with duodenal ulcer, there are a
number of causes for concern about their overzealous use as prophylactic agents:
symptomatic relapses can be treated with short (perhaps very short) courses of H2
blockers226 , 227; maintenance therapy is relatively expensive, costing the average
patient approximately $400 a year; and the long-term safety of H2 blockers has not been
established with certainty, since cimetidine has been on the market for only 13 years and
the other drugs for considerably shorter periods. For these reasons, many physicians
restrict maintenance therapy to patients with frequent symptomatic recurrences (three or
more a year), to patients who have had a complication of ulcer such as bleeding, or to
patients who are candidates for surgery but are at high surgical risk or refuse surgery.
Given in full doses, H2 blockers can prevent acute, endoscopically demonstrated
duodenal ulcers induced by nonsteroidal antiinflammatory drugs in patients with
arthritis.228 229 230 Whether this approach will prove cost effective in patients with no
history of duodenal ulcer is uncertain.

Gastric Ulcer
All four H2 blockers are effective in healing gastric ulcers in the doses shown in Table 1,
although only cimetidine and ranitidine are currently approved for this indication in the
United States.213 , 214 , 231 232 233 234 As shown in Figure 3, H2 blockers accelerate

the healing of gastric ulcers, with average rates of 63, 75, and 88 percent after four, six,
and eight weeks, respectively. Gastric ulcers heal more slowly than duodenal ulcers,212
probably in part because their average size is larger, but the rates after eight weeks are
nearly the same. Recent studies indicate that gastric ulcer (like duodenal ulcer) can be
successfully treated with a single dose of H2 blocker at bedtime.214 , 235 , 236 In one
study, which was not placebo controlled, the rate of healing of gastric ulcers with
ranitidine (150 mg twice a day) averaged 59 and 85 percent after four and eight weeks,
respectively, but only 32 and 53 percent in a subgroup of patients who were receiving
nonsteroidal antiinflammatory agents concurrently.237
Although H2 blockers are effective in accelerating the healing of gastric ulcers, the
evidence that they accelerate the relief of symptoms and prevent complications is less
convincing.213 Another goal of therapy is complete healing, since 2 to 5 percent of
gastric ulcers that appear benign are in fact malignant rather than peptic ulcers.213
Therefore, in a patient in whom a gastric ulcer persists after 8 to 12 weeks of H2-blocker
therapy or reappears soon after therapy is discontinued, gastric cancer should be
suspected.
Gastric ulcer, like duodenal ulcer, is a chronic, recurring disease, and relapses can be
prevented by maintenance therapy with H2 blockers.213 , 238 The caveats raised earlier
about maintenance therapy for duodenal ulcer apply to gastric ulcer as well. Furthermore,
none of the H2 blockers marketed in the United States have yet been approved for
maintenance therapy in patients with gastric ulcer. One area in which H2 blockers, even in
full doses, have been less effective is the prevention of acute gastric ulcers detected by
endoscopic surveillance in patients with arthritis who take nonsteroidal antiinflammatory
drugs.228 229 230 Prostaglandin analogues such as misoprostol may prove more
effective than H2 blockers in this setting.

Recurrent Ulcer after Surgery

Ulcers that recur after vagotomy, partial gastrectomy, or vagotomy plus partial gastric
resection respond better to H2 blockers than to placebo. In one review,239 the rates of
healing after four to six weeks ranged from 58 to 96 percent (median, 80) with cimetidine
(eight studies) or ranitidine (one study).

H2 Blockers in ZollingerEllison Syndrome

Before the mid-1970s, total gastrectomy was the therapy of choice for patients with
ZollingerEllison syndrome; more restricted operations did not reliably control the
hypersecretion of acid and prevent recurrent ulcer disease. With H2 blockers, the
hypersecretion of acid can be kept at safe levels (<10 mmol per hour in patients who have
not undergone surgery), although large doses of H2 blockers are usually required. Howard
et al. recently compared the effects of cimetidine, ranitidine, and famotidine on basal acid
hypersecretion in patients with the ZollingerEllison syndrome.240 The drugs were
given orally every six hours in doses sufficient to maintain the basal output of acid at less
than 10 mmol per hour. Ranitidine was 4 times more potent and famotidine 34 times

more potent than cimetidine. Famotidine was also 30 percent longer acting than
equipotent doses of cimetidine and ranitidine. Daily doses of up to 13.2 g of cimetidine,
3.6 g of ranitidine, or 480 mg of famotidine were required in some patients. In one
patient, basal acid hypersecretion could not be controlled with 14.4 g of cimetidine, 6.0 g
of ranitidine, or 640 mg of famotidine per day. Patients who are resistant to large doses of
H2 blockers are not rare, although the mechanism is uncertain. In some patients the H2
blocker is apparently not absorbed well, whereas in others the resistance seems to occur
at the level of the parietal cell.241 In these patients, basal hypersecretion of acid may
respond to the combination of an H2 blocker and an anticholinergic agent.240 , 242 Since
many patients now undergo laparotomy to search for tumors that can be resected,
parietal-cell vagotomy can be performed at the same time to reduce basal acid secretion
and facilitate postoperative therapy with H2 blockers.243 Given the need for large doses
of H2 blockers at frequent intervals to control the hypersecretion of acid, associated
adverse drug reactions, high cost, and inconvenience, some patients with the Zollinger
Ellison syndrome are now being switched to a hydrogenpotassiumATPase inhibitor
such as omeprazole.
H2 blockers may also be useful in treating patients with systemic mastocytosis and
urticaria pigmentosa and patients with basophilic leukemia, conditions characterized by
the excessive release of histamine from mast cells or basophils.244 , 245 Some of these
patients have hypersecretion of gastric acid and peptic ulcer disease as a result of
hyperhistaminemia.

H2 Blockers in Gastroesophageal Reflux Disease

The clinical spectrum of gastroesophageal reflux disease ranges from reflux symptoms
with no objective evidence of esophageal damage or inflammation to severe erosive and
ulcerative esophagitis with its associated complications (stricture, bleeding, and Barrett's
metaplasia with or without adenocarcinoma). Several factors determine whether
gastroesophageal reflux disease will develop in an individual patient: the amount of
gastric acid and pepsin that refluxes into the esophagus during a 24-hour period, the
length of time that acid and pepsin remain in the esophagus, and the intrinsic sensitivity
of the esophageal mucosa to damage by acid and pepsin.246 , 247
In some studies, 1.0 to 1.6 g of cimetidine per day, given in divided doses for 6 to 12
weeks, relieved the symptoms of reflux more rapidly than placebo,248 249 250 251 252
253 254 but in another study it did not.255 Substantial improvement in esophagitis,
assessed endoscopically and histologically, has not been demonstrated in the majority of
these studies. In contrast to duodenal ulcer and gastric ulcer, complete healing of
esophagitis with cimetidine is uncommon,248 , 251 , 253 254 255 even when cimetidine
is used in combination with metoclopramide.256
Unlike cimetidine, ranitidine is approved in the United States for use in patients with
gastroesophageal reflux disease. In one controlled study of 284 symptomatic patients
with endoscopic evidence of esophagitis, a positive Bernstein test, or both,257 ranitidine
(150 mg twice a day) relieved the symptoms of heartburn significantly more than

placebo, although the improvement was only moderate. Complete endoscopic healing
was achieved after six weeks in 56 percent of the patients taking ranitidine, as compared
with 41 percent of those taking placebo, a difference that was not significant. The authors
also detected no histologic improvement with ranitidine. The results of three smaller
placebo-controlled trials of ranitidine (150 mg twice a day) were similar.258 259 260
Combining data from the four studies257 258 259 260 gives an overall six-week rate of
healing with ranitidine of 47 percent, as compared with 26 percent with placebo. In a
recent multicenter study in Scandinavia confined to patients with erosive or ulcerative
esophagitis (or both), the rates of healing with ranitidine (150 mg twice a day) were 31
and 50 percent after four and eight weeks, respectively.261
Will higher-than-usual doses of H2 blockers, which presumably inhibit the secretion of
gastric acid more, lead to higher rates of healing of esophagitis? In 20 patients with
endoscopic evidence of esophagitis, the eight-week rates of healing with ranitidine were
similar whether 150 mg twice a day or double that dose was used (30 vs. 40 percent).262
In a study of 325 patients,263 a double dose of nizatidine (300 mg twice a day) led to
healing in 40 percent of the patients after six weeks, as compared with rates of healing of
30 percent with 300 mg of nizatidine at bedtime and 26 percent with placebo. The
corresponding rates of healing after 12 weeks were 50, 44, and 34 percent (P<0.05 for the
comparison of the high dose with placebo). Recently, Johnson et al. reported significantly
higher rates of healing with a quadruple dose of ranitidine (300 mg four times a day) than
with the standard dose (150 mg twice a day). The rates of healing after four and eight
weeks were 63 and 75 percent with the quadruple dose, as compared with 29 and 54
percent with the standard dose.264
If esophagitis does not heal with the usual doses of H2 blockers, will increasing the dose
result in improved healing? In 47 patients with esophagitis that was refractory to standard
doses of cimetidine or ranitidine, a double dose of ranitidine (300 mg twice a day)
resulted in healing after 4 and 12 weeks in 17 percent and 47 percent of the patients,
respectively. For comparison, in 51 similar patients randomly assigned to receive
omeprazole (40 mg in the morning), the rates of healing after 4 and 12 weeks were 63
percent and 90 percent, respectively.265
Koelz et al. treated 108 patients who had erosive or ulcerative esophagitis (or both) with
ranitidine in an uncontrolled study.266 The likelihood of healing was unrelated to sex,
age, weight, or duration of disease, but was related to the severity of esophagitis. For
example, healing of small erosions occurred in 28 of 36 patients (78 percent) within six
weeks, as compared with healing of moderate-sized erosions in 16 of 42 patients (38
percent) and healing of large erosions or ulcers in 10 of 30 patients (33 percent).
Likewise, Havelund et al. reported a healing rate of 88 percent after 12 weeks of
ranitidine (150 mg twice a day) in patients with mild disease, as compared with a rate of
only 54 percent in patients with moderate or severe disease (i.e., esophagitis with
erosions or ulcers).267
Once esophagitis is successfully healed with ranitidine, it is difficult to prevent relapse
with a maintenance dose (150 mg at bedtime).266 In patients with healed esophagitis, 36

percent of the placebo group relapsed within six months, as compared with 42 percent of
the group receiving maintenance ranitidine.266 Long-term, full-dose therapy is thus
generally required to prevent relapse of esophagitis.
Even if healing can be achieved with H2 blockers and relapses can be prevented, there is
no evidence that patients with gastroesophageal reflux disease who have Barrett's
metaplasia will have regression of the metaplasia with H2 blockers.268 269 270 The risk
of dysplasia and adenocarcinoma of the esophagus therefore remains considerable.
Whether prolonged therapy with omeprazole will lead to regression of Barrett's
metaplasia271 and reduce the risk of esophageal adenocarcinoma is uncertain.

H2 Blockers for Acute Stress Ulcers and Erosions

Within hours after major physical trauma (including extensive burns and major surgical
procedures) or after severe sepsis or another serious medical illness, mucosal ulcers,
erosions, or both almost invariably develop in the proximal stomach272 and sometimes
in the gastric antrum and duodenum. In 5 to 20 percent of patients with these conditions,
clinically important bleeding from these mucosal lesions develops, usually three to seven
days after the initial insult.272 , 273 These patients, usually admitted to an intensive care
unit, may have circulatory failure, respiratory failure requiring ventilatory support, renal
failure, liver dysfunction, coagulopathy, or central nervous system disease or injury. The
pathogenesis of mucosal damage and gastrointestinal bleeding is complex but, with the
exception of central nervous system injury, does not generally involve gastric
hypersecretion. Factors that may be pathogenetic include (but are not limited to) reduced
mucosal blood flow and oxygenation and reduced mucosal secretion of mucus and
bicarbonate.272 273 274 275
Intravenous H2 blockers (cimetidine, ranitidine, and famotidine) are widely used to
prevent stress ulcers in high-risk patients in intensive care units (nizatidine is not
available for parenteral use). Although several placebo-controlled studies (reviewed
below) have shown efficacy in this setting, the use of H2 blockers to prevent bleeding
from stress ulcers is not an approved indication in the United States. H2 blockers are also
widely used to treat stress ulcers associated with active bleeding. No controlled, doubleblind trials have yet demonstrated the superiority of H2 blockers (or antacid) over placebo
(or no therapy) in patients with active bleeding, however.
There is considerable information on the effects of H2 blockers, given in various doses
and by various methods (intermittent bolus doses and continuous infusions), on
intragastric pH, although many of these studies were not carried out in patients in
intensive care units. Although it is often assumed that maintaining intragastric pH above
4 will prevent stress ulcers (since peptic activity is quite low above pH 4), this has not
been proved conclusively. Thus, the exact relation between intragastric pH and the
prevalence of stress ulcers is not clearly established. For example, in a study of 44
patients receiving intensive care in which intravenous cimetidine given intermittently was
compared with intragastric antacid (Mylanta II), gastric pH was higher than 4 95 percent
of the time with antacid and only 79 percent of the time with cimetidine (P<0.001).

However, the prevalence of multiple fundic erosions on endoscopy was not significantly
different in the two groups (50 and 24 percent, respectively).276
Recently, Shuman et al. reviewed 16 published studies comparing intravenous cimetidine
given intermittently with placebo to prevent overt bleeding in patients in intensive care
units.277 They found that only 11 of 402 patients receiving cimetidine bled (3 percent),
as compared with 108 of 720 patients receiving placebo (15 percent) (P<0.001). They
also analyzed whether antacid therapy given through a nasogastric tube was superior to
cimetidine given intravenously in preventing bleeding. With antacid, the prevalence of
bleeding was 3 percent (15 of 450 patients), identical to the prevalence with cimetidine.
Shuman et al. concluded that cimetidine and antacid are equally effective in preventing
bleeding in patients in medical or surgical intensive care units. They provide evidence
that previous studies that reported a statistically significant superiority of antacids over
H2 blockers, such as one by Priebe et al.,278 came to this conclusion because they
included occult bleeding (i.e., bleeding detectable only by guaiac testing of gastric
aspirates) in their analyses. The clinical importance of occult bleeding in patients
receiving intensive care is uncertain.
It is easier to maintain intragastric pH above 4 by continuous intravenous infusion of
cimetidine than with intermittent bolus doses.279 , 280 This may produce better
prophylaxis of stress ulcers and gastrointestinal bleeding.280 Recently, Karlstadt et al.
reported that a continuous intravenous infusion of cimetidine (50 mg per hour after a 300mg bolus dose, increased to 100 mg per hour if gastric pH was below 4 for three hours)
was superior to placebo in preventing gross bleeding in 114 patients receiving intensive
care.281 The bleeding rate was 37 percent with placebo and 14 percent with cimetidine.
The mortality rates were similar in the two groups (placebo, 13 percent; cimetidine, 14
percent). In a similar subsequent study, the bleeding rate was 21 percent in patients given
placebo, as compared with only 2 percent in patients receiving 50 mg of cimetidine per
hour after a bolus injection of 300 mg. The mortality rate was 6 percent in both
groups.282
There are fewer data comparing H2 blockers with sucralfate in the prevention of stress
ulcers. In one study, among 130 patients with tracheal intubation who were randomly
assigned to receive sucralfate or various combinations of intravenous cimetidine,
intravenous ranitidine, antacids, or antacids plus an H2 blocker,283 gross bleeding
occurred in 2 patients in the sucralfate group and in 1 patient who received ranitidine. In
59 patients on mechanical ventilation who were treated with intravenous cimetidine,
sucralfate, or antacids, gross bleeding occurred in 5, 0, and 21 percent, respectively.284
In a third study,285 in which all 100 patients received pirenzepine, an antimuscarinic
agent, and sucralfate, cimetidine, or antacids, gross bleeding occurred in 0, 0, and 6
percent, respectively. These three studies and others286 287 288 289 suggest that
sucralfate is as effective as H2 blockers or intragastric antacids in preventing bleeding due
to stress ulcer.
Because the elevation of intragastric pH by H2 blockers or antacids may lead to bacterial
overgrowth in the stomach and retrograde colonization of the pharynx, predisposing the

patient to nosocomial pneumonia,290 there may be a theoretical advantage to using an

agent, such as sucralfate, that may prevent stress ulcers without raising gastric pH. In the
studies described above,283 284 285 the prevalence of nosocomial pneumonia in patients
treated with sucralfate was not significantly lower than the prevalence in patients
receiving H2 blockers, antacids, or both. In another study,286 the prevalence of
nosocomial pneumonia was significantly lower in the patients treated with sucralfate than
in those treated with antacids (10 vs. 34 percent), but it was similar in a small study
comparing sucralfate and ranitidine in patients receiving mechanical ventilation.289 We
believe that the evidence that sucralfate therapy is associated with less pulmonary
morbidity than H2 blocker therapy in patients in intensive care units is inconclusive.
In summary, intravenous cimetidine (and probably ranitidine and famotidine) given by
intermittent bolus or continuous infusion appears to be more effective than placebo in
preventing clinically important bleeding in patients in intensive care units and is
approximately as effective as intragastric antacids or sucralfate. None of these agents
reduce mortality rates in such patients. It will be of considerable interest to determine
whether proton-pump inhibitors, given in doses that keep intragastric pH at 7 or higher
throughout the day, will be more effective than H2 blockers or antacids in preventing or
treating upper gastrointestinal bleeding in patients in intensive care units and, if so,
whether these agents are safe and cost effective. The only currently approved indication
for intravenous cimetidine, ranitidine, or famotidine is a temporary inability to receive the
H2 blocker orally in patients with acceptable indications for oral therapy.

Conclusions
In general, the four H2 blockers are equally effective when equipotent doses are
prescribed. Considerable clinical experience has been gained with the use of cimetidine,
which can usually be used safely, except in patients taking other drugs whose metabolism
may be altered by cimetidine. The substantial, although somewhat more limited
experience with ranitidine indicates that it is also safe and that the risk of inhibiting the
metabolism of other drugs is considerably lower than with cimetidine. Although they are
newer, there is no evidence that famotidine and nizatidine have adverse effects that are
different from those of cimetidine and ranitidine, and they have less potential for drug
interactions. Patients in whom closer monitoring for adverse effects may be required
include the elderly, those with multiple medical problems (especially renal or hepatic
dysfunction), and those receiving drugs that may interact. All four agents are relatively
expensive. For example, an eight-week course of therapy in a patient with an active
peptic ulcer costs $98 to $116 in Dallas. Efficacy, safety, the potential for drug
interactions, and cost should be carefully considered when one is selecting an H2 blocker
for a particular patient.