Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports.

BACKGROUND: The process of generating 'signals' of possible unrecognized hazards from spontaneous adverse drug reaction reporting data has been likened to looking for a needle in a haystack. However, statistical approaches to the data have been under-utilised. METHODS: Using the UK Yellow Card database, we have developed and evaluated a statistical aid to signal generation called a Proportional Reporting Ratio (PRR). The proportion of all reactions to a drug which are for a particular medical condition of interest is compared to the same proportion for all drugs in the database, in a 2 x 2 table. We investigated a group of newly-marketed drugs using as minimum criteria for a signal, 3 or more cases, PRR at least 2, chi-squared of at least 4. FINDINGS: The database was used to examine retrospectively 15 drugs newly-marketed in the UK, with the highest levels of ADR reporting. The method identified 481 signals meeting the minimum criteria during the period 1996-8. Further evaluation of these showed that 70% were known adverse reactions, 13% were events which were likely to be related to the underlying disease and 17% were signals requiring further evaluation. IMPLICATIONS: Proportional reporting ratios are a valuable aid to signal generation from spontaneous reporting data which are easy to calculate and interpret, and various refinements are possible.

Severe cystitis associated with tiaprofenic acid.

OBJECTIVE: To review the UK spontaneous reports of urinary disorders associated with tiaprofenic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) and put them into context of the usage of these preparations in the UK. METHODS: Suspected adverse drug reaction (ADR) reports of urinary disorders associated with tiaprofenic acid and other NSAIDs received by the UKs spontaneous ADR reporting scheme were analysed. RESULTS: Between 1982, when tiaprofenic acid was introduced in the UK, and August 1994, 69 cases of cystitis were reported, with a further 32 reports describing related urinary symptoms including frequency, dysuria and haematuria. Only eight cases of cystitis were reported for all other NSAIDs. The duration of treatment with tiaprofenic acid before the onset of urinary symptoms varied markedly (range 2 days to > 3 years). In patients in whom a drug-induced cause was suspected and the drug was stopped promptly, recovery usually occurred within weeks. However, many patients continued on long-term treatment with tiaprofenic acid and underwent extensive investigations to determine the cause of their urinary symptoms. On cystoscopy and biopsy, the findings were similar to interstitial cystitis. Most patients with chronic cystitis recovered after withdrawal of tiaprofenic acid, but some patients had surgery before the drug was stopped. CONCLUSION: Tiaprofenic acid can cause severe cystitis. These reports highlight the importance of taking a full drug history in patients with unexplained chronic cystitis. Tiaprofenic acid should be stopped immediately in all patients developing urinary symptoms.

A comparison of the post-marketing safety of four selective serotonin re-uptake inhibitors including the investigation of symptoms occurring on withdrawal.

1. We have addressed the question of whether there is a 'serotonin withdrawal syndrome' by analysis of spontaneous reports of suspected adverse drug reactions (ADRs) associated with four SSRIs. A comparison of the post-marketing safety profiles of the four SSRIs has also been made. 2. The UK database of ADRs was examined for reactions associated with fluoxetine, fluvoxamine, paroxetine and sertraline. The safety profiles of the four SSRIs were similar. However, withdrawal reactions with paroxetine constitute a greater proportion of reports (5.1%) than with the other SSRIs (0.06-0.9%). They have been reported more often with paroxetine (0.3 reports per thousand prescriptions) than with sertraline and fluvoxamine (0.03), and least often with fluoxetine (0.002). 3. Descriptions of withdrawal reactions received and further details of 217 reports of withdrawal reaction with paroxetine obtained by mailing a questionnaire to the reporting doctor were examined. Withdrawal symptoms were diverse but most commonly comprised dizziness, paraesthesia, tremor, anxiety, nausea and palpitation. They usually occurred after 2 days and lasted for an average of 10 days. There was no evidence of a physical drug dependency syndrome. 4. Symptoms different from the previous depressive illness occur after discontinuing an SSRI, and are reported most often with paroxetine. Paroxetine is the most pharmacologically specific of the SSRIs, but it is not clear whether the reactions constitute a 'serotonin withdrawal syndrome'.

Appetite suppressants and primary pulmonary hypertension in the United Kingdom.

OBJECTIVE: Amphetamine-like appetite suppressants, particularly fenfluramines, have been implicated in the aetiology of primary pulmonary hypertension. At one specialist centre in France 20% of patients with primary pulmonary hypertension had been exposed to fenfluramine. The prevalence of primary pulmonary hypertension associated with fenfluramines and other appetite suppressants in the United Kingdom is unknown. This study was performed to measure prior exposure to appetite suppressants in patients with primary pulmonary hypertension. SETTING: Heart lung transplantation centres in England. PATIENTS: United Kingdom residents with proven primary pulmonary hypertension referred for consideration of heart lung transplantation. METHODS: Case surveillance study, obtaining data from the hospital and general practitioner's notes and directly from the patients or their relatives. RESULTS: 55 patients were identified. Drug histories were available from hospital records in all patients, from the general practitioner's notes in 51, and from the patients or relatives in 44. Of these, 3 female patients had been exposed to appetite suppressants (2 fenfluramine, 1 diethylpropion): 2 have since died. In each case exposure was brief and apparently predated the development of symptoms by several years. CONCLUSIONS: Exposure of patients with severe primary pulmonary hypertension to fenfluramine and other appetite suppressants is uncommon in the United Kingdom unlike in France, where most of the cases associating primary pulmonary hypertension with fenfluramine use have originated. This may reflect more conservative prescribing of these agents in the United Kingdom.

Effects of atenolol withdrawal in patients on triple antihypertensive therapy.

The objective of this study was to examine the contribution of beta-blockade to antihypertensive treatment regimens including an angiotensin converting enzyme inhibitor or a calcium antagonist. The effects on BP control, adverse events, and plasma active renin concentration of removing atenolol from standard triple therapy (bendrofluazide and atenolol together with captopril or nifedipine) were assessed in a double-blind, randomised, parallel-group study, of eight weeks' duration in 46 patients from the Glasgow Blood Pressure Clinic. Blood pressures rose in patients randomised to placebo-atenolol compared with those who continued active-atenolol although the difference did not achieve statistical significance. However, the proportion of patients with controlled blood pressure (supine systolic BP < 140 mmHg plus supine diastolic BP < 95 mmHg) fell from 31% to 0% over the study period in patients given placebo-atenolol. There was a trend for BP control to deteriorate most when atenolol was withdrawn from nifedipine treated patients, but the 95% confidence intervals for the difference from captopril-treated patients were wide. Few side-effects were seen and these did not differ quantitatively between the study groups. Plasma active renin concentration was initially higher in captopril-treated patients, and increased on withdrawal of atenolol in both groups. Our findings suggest that beta-blockers make a clinically relevant contribution to treatment regimens including angiotensin converting enzyme inhibitors or calcium antagonists when given as part of standard triple antihypertensive therapy.

Comparison of captopril, hydralazine and nifedipine as third drug in hypertensive patients.

The antihypertensive, biochemical and adverse effects of captopril, hydralazine, nifedipine and placebo were compared in 160 patients with BP inadequately controlled by atenolol 100 mg daily plus bendrofluazide 5 mg daily. Treatments were given for up to 12 weeks. Beta-blocker and thiazide were continued unchanged. All three active drugs reduced supine BP relative to placebo; mean BP changes attributable to active treatment (95% confidence intervals): captopril 13.4/10.3 mmHg (0.6/4.0 to 26.2/16.6), hydralazine 15.0/10.0 mmHg (1.7/3.4 to 28.3/16.6), nifedipine 16.8/8.1 mmHg (4.0/1.8 to 29.6/14.4). There were no significant differences between the agents. Results for erect BP were similar. Target BP (< 140/95 mmHg) was achieved more frequently on captopril (33%), hydralazine (29%) and nifedipine (17%) than on placebo (10%). Compared with the other treatments captopril increased serum potassium concentration (P = 0.01), and hydralazine reduced serum cholesterol concentration (median changes: captopril -0.2 mmol/l, hydralazine -0.8 mmol/l, nifedipine -0.2 mmol/l, and placebo +0.2 mmol/l, P < 0.001). Overall, side-effects did not differ significantly between the groups; withdrawals resulting from adverse reactions: captopril 15%, hydralazine 24%, nifedipine 22%, and placebo 3% (chi 2 = 8.2, P = 0.04). Captopril, hydralazine and nifedipine did not differ significantly in efficacy and tolerability when added to atenolol and bendrofluazide. However, there were trends in favour of captopril, on which drug the highest proportion of patients had their BP controlled and the lowest proportion were withdrawn because of side-effects. Thus, of the drugs tested, captopril appears to be the best option as third drug in hypertension.

Review of company postmarketing surveillance studies.

OBJECTIVES: To review postmarketing surveillance studies sponsored by the pharmaceutical industry since the introduction of voluntary guidelines in 1987 and to evaluate their contribution to monitoring drug safety. DESIGN: Retrospective analysis of the information submitted to the Medicines Control Agency on postmarketing surveillance studies. SETTING: United Kingdom. MAIN OUTCOME MEASURES: Study designs, projected and actual sample sizes, provision of interim and final reports, number of suspected serious adverse reactions reported, identification of new drug safety hazards. RESULTS: 31 studies had been conducted under the guidelines, of which 27 were prospective and four retrospective. Nine studies had at least one comparator group, the remainder were uncontrolled. The median projected sample size for the studies was 5600 patients. Only five studies had achieved at least 75% of the projected sample size. 11 studies had been abandoned, predominantly because of difficulties in recruitment, and 15 were ongoing. One study had identified an important new safety hazard. CONCLUSIONS: Company postmarketing surveillance studies have made only a limited contribution to the assessment of drug safety, principally because of weak study designs and difficulties in recruitment. The guidelines require modification to take this experience into account.

Pharmacological approaches to the treatment of intermittent claudication.

Intermittent claudication is a common condition of the elderly, occurring in 3 to 20% of individuals over the age of 65 years. Although local disease is usually benign, life expectancy in patients with intermittent claudication is reduced by approximately 10 years due to associated cardiovascular mortality. Several classes of drugs have been used in intermittent claudication, but clinical studies evaluating their efficacy leave much to be desired. Pentoxifylline (oxpentifylline), a rheological agent, and naftidrofuryl, an enhancer of aerobic metabolism, are the 2 most widely investigated and utilised drugs. The combined results of 10 placebo-controlled studies with pentoxifylline and 4 with naftidrofuryl estimate increases in claudication distances of 51 and 42%, respectively. However, due to publication bias, these figures are probably overestimates of the true benefit from treatment with these drugs. It is likely that any benefit from pentoxifylline or naftidrofuryl is small and of little clinical importance. The suggestion that naftidrofuryl has greater efficacy in older patients remains unproven. Other classes of drugs including vasodilators, antiplatelet drugs, anticoagulants and prostaglandins have not been shown to be effective. Only 2 approaches to the management of intermittent claudication have been shown convincingly to be of benefit: stopping smoking and exercising regularly.

Policies for managing hypertensive patients: a survey of the opinions of British specialists.

In September 1988 medically-qualified members of the British Hypertension Society were asked to complete anonymously a questionnaire relating to their views on the management of hypertensive patients. Of 149 questionnaires posted, 90 were returned (60%). There was general agreement that non-pharmacological measures, particularly weight loss and alcohol restriction, are effective treatments. However, there was wide variation in the minimum level of blood pressure considered to warrant drug treatment and little consensus regarding measurement policies or target blood pressures. The drugs of first choice were beta-blockers (54% in men, 35% in women) and thiazide diuretics (28% in men and 47% in women), and they were also the most frequent second choices with 54% of respondents advocating 'stepped-care' based on these drugs. The maximum age at which respondents would be prepared to introduce antihypertensive drugs varied widely although 63% considered that thiazide diuretics are first choice in the elderly. These findings demonstrate a broad range of opinion on the management of hypertension among British specialists, and suggest a continuing need for large clinical trials.