Gordon Murray

Captopril in heart failure. A double blind controlled trial.

The effect of the converting enzyme inhibitor captopril as long term treatment was investigated in 14 patients with severe congestive heart failure in a double blind trial. Captopril reduced plasma concentrations of angiotensin II and noradrenaline, with a converse increase in active renin concentration. Effective renal plasma flow increased and renal vascular resistance fell; glomerular filtration rate did not change. Serum urea and creatinine concentrations rose. Both serum and total body potassium contents increased; there were no long term changes in serum concentration or total body content of sodium. Exercise tolerance was appreciably improved, and dyspnoea and fatigue lessened. Left ventricular end systolic and end diastolic dimensions were reduced. There was an appreciable reduction in complex ventricular ectopic rhythms. Adverse effects were few: weight gain and fluid retention were evident in five patients when captopril was introduced and two patients initially experienced mild postural dizziness; rashes in two patients did not recur when the drug was reintroduced at a lower dose; there was a significant reduction in white cell count overall, but the lowest individual white cell count was 4000 X 10(6)/l. Captopril thus seemed to be of considerable value in the long term treatment of severe cardiac failure.

The fate of the claudicant—a prospective study of 1969 claudicants

A prospective study of 1969 patients with intermittent claudication receiving placebo medication for a minimum of 1 year is reported. Patients were carefully monitored and only four patients were lost to follow-up. Annual mortality was 4.3%. Thirty-six patients developed a definite myocardial infarction, 27 a major stroke, 32 required a major amputation and 111 required surgical or radiological intervention for deteriorating ischaemia of the leg. The entry characteristics of the patients were analysed as a predictor of serious cardiovascular events. The most sensitive predictors of total mortality were age, history of coronary heart disease and an ankle/arm pressure ratio below 0.5. Of the laboratory measurements performed only the initial white cell count was a significant predictor of myocardial infarction, stroke and vascular deaths.

Correcting for the bias caused by drop‐outs in hypertension trials

A major source of bias in hypertension trials can arise from patients who are withdrawn during the course of the trial because of inadequate blood pressure control. We develop a mechanism which allows for such withdrawals while preserving the potential to make an unbiased comparison of the treatment effects. The approach is illustrated using data from a large multicentre trial of two anti-hypertensive agents in patients with mild to moderate essential hypertension.

The Carvedilol Hibernation Reversible Ischaemia Trial; Marker of Success (CHRISTMAS)†

Carvedilol improves left ventricular (LV) function when heart failure is due to LV systolic dysfunction, but the magnitude of the response is heterogeneous among patients with coronary disease, possibly reflecting the presence or volume of hibernating myocardium. Aims: The primary objective of the study is to determine whether the presence of hibernating myocardium predicts the magnitude of improvement in LV ejection fraction in response to carvedilol among patients with heart failure and LV systolic dysfunction due to coronary disease.

International study of ketanserin in Raynaud's phenomenon

PURPOSE The effects of ketanserin on primary or secondary Raynauds phenomenon due to connective tissue disease were studied in a large, international group of patients. PATIENTS AND METHODS The study population consisted of 222 patients from 10 countries. After a run-in period of one month of placebo therapy, patients were randomly assigned in a double-blind manner to receive ketanserin 40 mg three times daily (n = 113) or placebo (n = 109) for three months. Total finger blood flow was measured in 41 patients in a warm and cool room before and during treatment. Vasospastic episodes were assessed by diaries and global evaluations. RESULTS A significant reduction of 34% in frequency of episodes occurred with ketanserin, compared to 18% with placebo (p = 0.011). There was a 1% reduction in duration of episodes with ketanserin therapy, compared to a 2% increase with placebo therapy, but this finding was not statistically significant (p = 0.29). No difference was observed in severity of attacks. Global evaluations by investigators (p = 0.03) and patients (p less than 0.01) showed an overall benefit with ketanserin compared to that seen with placebo. Patients with primary or secondary Raynauds phenomenon responded similarly to treatment. No changes in total finger blood flow were found. CONCLUSION Ketanserin significantly improves the subjective symptoms of patients with primary or secondary Raynauds phenomenon and is an appropriate agent to use in this disease when conservative measures fail.

EFFECT OF THE SURGEON'S SPECIALITY INTEREST ON THE TYPE OF RESECTION PERFORMED FOR COLORECTAL CANCER

PURPOSE: The aim of this study was to examine the type of resection performed for colorectal cancer by surgeons with a colorectal interest and compare this with the type of resection performed by surgeons with other specialty interests. METHODS: One hundred sixteen patients had curative surgery performed for primary colorectal cancer over a one-year period by ten surgeons with four different specialty interests. RESULTS: Surgeons with an interest in colorectal cancer resected twice as much colon (280 mmvs.130 mm;P>0.0001, Mann-WhitneyUtest) and were more likely to remove adjacent clinically involved organs (15 percentvs.0 percent) for left-sided colon and rectal cancers compared with surgeons with vascular or transplant interests. Surgeons with an interest in gastroenterology performed a resection that was intermediate between the colorectal and other specialty groups for left-sided cancers. Distal resection margins were significantly greater (55 mmvs.20 mm;P>0.001) for sigmoid cancers in the colorectal group, but were similar in all groups for rectal cancer. Resection lengths and margins for right-sided cancers were similar in all groups, although the number of lymph nodes retrieved from the mesentry was greater in the colorectal group (13vs.7.5;P=0.08). CONCLUSION: This study shows a wide variability in the type of resection performed for colorectal cancer and illustrates the need for clinical trials to evaluate the effect of such variability on patient outcome.

Enalapril in Treatment of Hypertension with Renal Artery Stenosis: Changes in Blood Pressure, Renin, Angiotensin I and II, Renal Function, and Body Composition

The converting enzyme inhibitor enalapril, in single daily doses of 10 to 40 mg, was given to 20 hypertensive patients with renal artery stenosis. The decrease in blood pressure six hours after the first dose of enalapril was significantly related to the pretreatment plasma concentrations of active renin and angiotensin II, and to the concurrent decrease in angiotensin II. Blood pressure decreased further with continued treatment; the long-term decrease was not significantly related to pretreatment plasma renin or angiotensin II levels. At three months, 24 hours after the last dose of enalapril, blood pressure, plasma angiotensin II, and converting enzyme activity remained low, and active renin and angiotensin I high; six hours after dosing, angiotensin II had, however, decreased further. The increase in active renin during long-term treatment was proportionately greater than the increase in angiotensin I; this probably reflects the diminution in renin substrate that occurs with converting enzyme inhibition. Long-term enalapril treatment increased renin secretion by more than 10-fold, and renal venous and peripheral plasma renin concentration by more than 20-fold; however, the mean renal venous renin ratio was not changed. Enalapril caused a reduction in effective renal plasma flow via the affected kidney but a marked and consistent increase on the contralateral side, where renal vascular resistance decreased. The overall increase in effective renal plasma flow was significantly related to the decrease in angiotensin II. Overall glomerular filtration rate was lowered, and serum creatinine and urea increased. Enalapril alone caused a long-term reduction in exchangeable sodium, with slight but distinct increases in serum potassium. In five patients with bilateral renal artery lesions, enalapril given alone for three months did not cause renal function to deteriorate. Enalapril was well tolerated and provided effective long-term control of hypertension; only two of the 20 patients studied required concomitant diuretic treatment.

Similarity of idiopathic aldosteronism and essential hypertension. A statistical comparison.

There is clinical, biochemical, and pathological evidence that idiopathic aldosteronism is part of a continuum which includes low-renin and normal-renin essential hypertension. In a retrospective statistical study, 89 patients with essential hypertension have been compared with 22 cases of idiopathic aldosteronism and 34 cases of aldosterone-secreting adrenal adenomas. Measurements of serum sodium, potassium, bicarbonate, and plasma angiotensin II concentrations and estimates of exchangeable sodium and potassium were obtained for individual patients. By using various combinations of these biochemical variables, a statistic, the Mahalanobis distance, was described for each of the three populations, essential hypertension, idiopathic aldosteronism, and adrenal adenomas. For each combination of variables, the distribution of the idiopathic aldosteronism group resembled that of the essential hypertension group more closely than that of the aldosterone-secreting adrenal adenoma group. Thus, the use of this statistical technique provides further evidence of the similarity of essential hypertension and idiopathic aldosteronism.

Combination of verapamil and beta blockers in systemic hypertension

The efficacy and safety of verapamil and propranolol were examined in 14 hypertensive patients (mean age 51.2, range 30 to 65) in a double-blind, randomized, crossover study of verapamil, 360 mg, propranolol, 240 mg, these 2 formulations in combination and placebo, each given for 4 weeks. Supine blood pressure, heart rate, atrioventricular conduction (PR interval) and left ventricular function were measured. All treatments reduced diastolic blood pressure (mean +/- standard deviation) (p less than 0.001): placebo to 106.6 +/- 8.1 mm Hg; propranolol to 93.8 +/- 7.7; verapamil to 89.8 +/- 7.8; the combination to 84.1 +/- 6.1, but the effect of the combination was significantly greater than that of either drug alone (p less than 0.05). Heart rate at rest (placebo, 80.2 +/- 12.2 beats/min) was reduced by propranolol (63.3 +/- 9.4, p less than 0.001), but not by verapamil (79.0 +/- 8.9). However, the addition of verapamil to propranolol led to a further reduction in heart rate (56.9 +/- 8.4, p less than 0.005). PR interval was prolonged significantly by the combination (185.5 +/- 35.3 ms) when compared with placebo (154.0 +/- 22.7); propranolol (159.1 +/- 21.2) and verapamil (165.5 +/- 32.4) (p less than 0.005 for each). The active drugs increased end-diastolic dimension and end-systolic dimension. For each variable, the effect of the combination was statistically significant (p less than 0.01). Fractional shortening was not altered significantly by any of the treatments. Thus verapamil plus propranolol is a very effective antihypertensive combination but heart rate, atrioventricular conduction and left ventricular function may be affected adversely, necessitating careful monitoring of therapy.

Haemostatic abnormalities and outcome in patients with operable breast cancer

The predictive value for cancer recurrence of five measurements of haemostatic activity was studied in 89 patients with operable breast cancer. Neither preoperative nor sequential measurements up to 9 months postoperatively of fibrinopeptide A, fibrin fragment B beta 15-42, fibrinogen and serum fibrin(ogen) degradation products nor the fibrin plate lysis assay correlated with early recurrent disease. B beta 15-42 values were higher preoperatively in patients with oestrogen receptor positive tumours (P = 0.017). Mean B beta 15-42 values rose postoperatively (P = 0.003), largely because of an increase in patients with oestrogen receptor negative tumours.