Biotech Tracker News - ALLHAT Studies will Impact Use of Non-Thiazides More than Use of Statins
December 19, 2002 Two large-scale studies published in this week’s Journal of the American Medical Association (JAMA) have captured considerable attention in the general public. The studies highlight a trend to compare drugs that target similar patient populations. The null hypotheses of these studies are often that older, less expensive drugs are just as good as newer, more expensive drugs. In some cases, this hypothesis will be rejected, supporting the more innovative product. In other cases, this hypothesis will be validated and that validation will be subject to further analytic scrutiny in order characterize its validity as internal, external, or both. The degree of external validity (for which internal validity is a prerequisite) is the degree of generalizability, and characterizes the extent to which the findings can or should be applied to the practice of medicine on a population basis.  Studies like the two JAMA studies will become more frequent given the increasing demand for improved resource allocation in the health care and biomedical industries. Studies like these will be a source of pressure on the pharmaceutical and biotechnology industries as they struggle to meet the demands of providing innovative medicines that impact disease more favorably than their predecessors. Analysis of studies like these require high-profile critical appraisal in order to project their impact on utilization, reimbursement, and sales trends.  Both JAMA studies are out of investigation of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial cohort. The first study’s conclusion is that cheap, old, Thiazide-type diuretics (“water pills”) are just as effective as newer antihypertensives such as calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors. Dr. Jackson T. Wright Jr., vice-chairman of the ALLHAT steering committee, went so far as to say that, “They are unsurpassed at lowering blood pressure and reducing the clinical complications of hypertension. Furthermore, they are well tolerated by patients and they cost less.”  The second study’s conclusion is that pravastatin (Bristol-Myers Squibb’s Pravachol) does not provide vastly superior clinical outcomes compared to “usual care” for patients with high cholesterol. However, Dr. Jeffrey L. Probstfield, steering committee director for the second study, said, “As a physician whose clinical activities focus on those with high lipids, particularly high cholesterol, my final recommendation is to continue to take and prescribe cholesterol-lowering drugs, particularly statins… this will reduce the rate of coronary heart disease and deaths.” On balance, the first study is likely to have a more significant impact on the use of non-thiazides for hypertension than the second study will have on the use of statins. ALLHAT: Thiazides for the initial therapy of hypertension, a 4-year study 42,418 men and women 55 years of age or older with hypertension and at least one other risk factor for coronary heart disease were randomized to receive chlorthalidone (12.5 mg to 25 mg/day of a thiazide, sold as Hygroton from Novartis and Thalitone from King), amlodipine (2.5 mg to 10 mg/day of a calcium channel blocker sold as Lotrel from Novartis and Norvasc from Pfizer) or lisinopril (10 mg to 40 mg/day of an ACE inhibitor sold as formulations from Merck and AstraZeneca). An alpha-adrenergic blocker was also a part of this study, but that arm was stopped in March 2000 because recipients experienced 25% more cardiovascular events and were twice as likely to be hospitalized for heart failure compared to thiazide recipients. Mean follow-up time was 4.9 years.  No significant differences in outcomes were seen between the amlodipine and chlorthalidone arms for the endpoints of: fatal coronary heart disease (CHD) or non-fatal myocardial infarction (MI, heart attack)  all-cause mortality  combined CHD, stroke  combined CVD, angina, coronary revascularization, peripheral arterial disease, cancer or end-stage renal disease (ESRD).  Moreover, the amlodipine group also had a 38% greater risk of heart failure.  No significant differences in outcomes were seen between the lisinopril and chlorthalidone arms for the endpoints of:  fatal CHD or non-fatal MI  all-cause mortality  combined CHD, peripheral arterial disease, cancer or ESRD.  The lisinopril group had a 15% higher risk of stroke and a 10% higher risk of combined cardiovascular disease.  The generalizability of the results is enhanced by earlier findings of no significant differences in CHD and stroke rates observed between chlorthalidone- and amlodipine-based intervention. Earlier investigation also support the increased heart failure rate for amlodipine recipients. The lower heart failure incidence for thiazide diuretics is also well-substantiated.  Dr. Lawrence J. Appel, of Johns Hopkins University hit the nail on the head in terms of payor perception, for this specific clinical scenario, in an accompanying editorial indicating that, “ALLHAT results...are particularly noteworthy, because there is no cost-quality tradeoff; the most effective therapy was also the least expensive…it is unclear why physicians should implement an ACE inhibitor-based strategy that commonly leads to use of two drugs (ACE inhibitor and diuretic) when monotherapy with a thiazide diuretic can effectively reduce blood pressure and prevent blood pressure-related cardiovascular outcomes.” ALLHAT: Pravastatin for cholesterol management, an 8-year study Investigators evaluated 10,355 patients, 55 years of age or older, with low-density lipoprotein (LDL, “bad” cholesterol) levels of 120 mg/dL to 890 mg/dL and triglycerides levels lower than 350 mg/dL. Study subjects were randomized to receive Pravastatin 40 mg per day or “usual care.” Mean follow-up was 4.8 years. At the fourth year, Pravastatin was found to do what it was supposed to do. Total cholesterol was down 17.2% for pravastatin recipients versus 7.6% with “usual care.” LDL was down 27.7% versus 11.0% for Pravastatin and “usual care” recipients, respectively. However, the primary endpoint of all-cause mortality did not differ significantly between the two treatment groups. Similar rates of both cardiovascular death and 6-year incident cancer were observed. Overall CHD and stroke were somewhat lower in the pravastatin group.  The study observations that appear to diminish the generalizability of the observations, and thus the impact on use, reimbursement, and sales patterns were:  smaller than expected difference in total cholesterol levels between groups  nonblinded study design  protocol switching by year 6 70.3% of those randomized to pravisatatin were still taking 40 mg of the agent  28.5% of the usual care group was actually receiving a lipid-lower drug, 26.1% a statin.  An accompanying editorial by Dr. Richard C. Pasternak of Massachusetts General Hospital and Harvard Medical School highlights these aspects of protocol switching. Dr. Pasternak writes, “Did all of those randomly selected actually have testing, or could those returning for testing have been more motivated to be tested because of their concurrent adherence to therapy? If adherent patients were more likely to return for LDL testing, the differential could be even smaller than the 16.7% reported, further explaining the similar outcomes.”  Given the suspect generalizability and understanding that numerous investigations demonstrate poor compliance with statins, Dr. Pasternak felt that the results of ALLHAT, “point to the need for improved adherence and understanding reasons for nonadherence,” cautioning doctors to read and appraise these results with extreme care.  Thiazides are sold by Novartis, Merck, Pfizer, Parke-Davis, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Wyeth, Bertek, Boehringer Ingelheim, Watson, Schwarz, Lederle, Mylan, Geneva, Endo Generics, Par, Roxane, King, Wallace, Celltech, and Monarch. Statins are sold by Pfizer, Merck, Novartis, and Bristol-Myers Squibb. AstraZeneca’s Crestor has been approved in Holland and is being reviewed for approval in many other worldwide markets.
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